JP7194530B2 - Highly permeable prodrug compositions of peptides and peptide-related compounds - Google Patents

Description

Cross-reference to related applications

PRIORITY CLAIM This application is a continuation-in-part of and claims priority to US patent application Ser. No. 12/463,374, filed May 8, 2009, which is incorporated herein by reference. This application also claims priority from Chinese Patent Application No. 200910135997.0 filed on May 8, 2009.

TECHNICAL FIELD This invention is in the field of pharmaceutical compositions capable of penetrating one or more biological barriers and preventing, diagnosing and treating conditions or diseases in humans and animals that are treatable by peptides or peptide-related compounds. /or to methods of using the pharmaceutical compositions for treatment. The invention also relates to methods of using the pharmaceutical compositions for screening new drug candidates and methods of using the pharmaceutical compositions for diagnosing conditions in living subjects. Methods have been developed to synthesize N-terminal to C-terminal peptide HPPs/HPCs.

Peptides are polymers formed by linking amino acids with amide bonds. Peptides play a variety of roles in biological systems. For example, peptide hormones are the largest group of hormones that regulate various biological processes in living subjects. One nanogram of thyrotropin-releasing hormone injected into mice enhances the uptake of iodine from the blood into the thyroid (R.L. ^Kisliuk , Principles of Medicinal Chemistry, 4th Ed., W.O. Foye, et al. Eds. ., Williams & Wilkins, 4th ^Ed . 1995, p. 606). Tufutosin (Thr-Lys-Pro-Arg) stimulates phagocytosis and promotes antibody-dependent cytotoxicity (VA Najjar, Mol. Cell. Biochem. 41 , 1, 1981). Met-enkephalin (Tyr-Gly-Gly-Phe-Met), isolated from the brain and small intestine, acts like morphine in that it binds to the same receptors and has analgesic activity (JR Jaffe and W. R. Martin, in Pharmaceutical Basis of Therapeutics, A. G. Gilman, et al., Eds., New York, Pergamon Press, 1990, p. 481). Other examples of peptide hormones include, but are not limited to, oxytocin (Pierce et al., J. Biol. Chem. 199 , 929, 1952), vasopressin (Kamm et al., J. Am. Chem. Soc. 50 , 573, 1928), angiotensin (J.C. Garrison and M.J. Peach, in Pharmacological Basis of Therapeutics, A.G. Gilman, et al., Eds., New York, Pergamon Press, 1994, p. 9) , Gastrin (P.C. Emson and B.E.B. Sandberg, Annu, Rep. Med. Chem., 18 , 31, 1983), Somatostatin (A.V. Schally, et al., Annu. Rev. Biochem ., 47 , 89, 1978), dynorphin (MG Weisskopf, et al., Nature, 362 , 423, 1993), endothelin (A.M. Doherty, J. Med. Chem., 35 , 1493, 1992), secretin (E. Jorper, Gastroenterology, 55 , 157, 1968), calcitonin (M.V.L. Ray, et al., Biotechnology, 11 , 64, 1993), insulin (F. Sanger, Br. Med. Bull., 16 , 183, 1960), and competence stimulating peptides (CSPs).

Another group of peptides are antimicrobial peptides that have been found to participate in innate immunity in a wide variety of organisms (Reddy et al. 2004). These peptides and others are of great interest because of their potential utility in treating infections, especially since they are often effective against bacterial strains that have become resistant to conventional antibiotics. attracting. One well-known class of antimicrobial peptides is the tachyplesins. Another class of antimicrobial peptides are histatin peptides and their derivatives. Another class of antimicrobial peptides is hepcidin, also called LEAP-1 for antimicrobial peptides expressed in the liver.

Another group of peptides are calcium-binding peptides that specifically bind to calcified surfaces. An example of a calcium-binding peptide contains a repeat sequence of three amino acids (XYZ) _n , where X is aspartic acid, glutamic acid, asparagine or glutamine, Y and Z are alanine, serine, threonine, Phosphoserine or phosphothreonine, n is a number from 1-40.

Unfortunately, peptides and peptide-related compounds are rapidly proteolyzed by proteolytic enzymes. When peptides and peptide-related compounds are taken orally, they undergo proteolysis within minutes. Other systemic administrations of peptides and peptide-related compounds are painful and often require frequent and costly office visits to treat chronic conditions.

Thus, for novel compositions that can be efficiently and effectively delivered to the site of action of a condition (e.g., disease) to prevent, alleviate, or treat the condition while minimizing adverse side effects. A need exists in the art.

One aspect of the present invention is directed to hyperpermeable prodrugs (HPPs) or hyperpermeable compositions (HPCs) comprising a functional unit covalently attached to a transport unit via a linker. The terms "HPP" and "HPC" are used herein alone or together and are interchangeable unless otherwise stated.

In certain embodiments, the HPP or HPC functional unit comprises an agent moiety, wherein efficient and effective delivery of the agent to a biological subject and/or transport of the agent across one or more biological barriers is desired.

In certain embodiments, functional units may be hydrophilic, lipophilic or amphiphilic (ie, both hydrophilic and lipophilic). For example, the lipophilic nature of the functional unit may be inherent or achieved by converting the hydrophilic portion of the functional unit into a lipophilic portion.

In certain embodiments, functional units of HPP or HPC comprise portions of peptides or peptide-related compounds. Peptide-related compounds are compounds containing peptide structures, peptide metabolites, or agents that can be metabolized to peptides or peptide metabolites after HPP or HPC permeates one or more biological barriers. Peptide-related compounds are also peptides or peptide metabolite analogs or mimetics, or agents that can be metabolized to peptides or peptide metabolite analogs or mimetics after HPP or HPC permeates one or more biological barriers. Contains a compound. Examples of peptides include peptide hormones (eg Thyrotropin Releasing Hormone, Tuftsin (Thr-Lys-Pro-Arg), Met-Enkephalin (Tyr-Gly-Gly-Phe-Met), Oxytocin, Angiotensin, Gastrin, Somatostatin, Dynotropin). Ruphin, endothelin, secretin, calcitonin and insulin), enterostatin (e.g. Val-Pro-Asp-Pro-Arg (VPDPR), Val-Pro-Gly-Pro-Arg (VPGPR) and Ala-Pro-Gly-Pro- Arg(APGPR)), melanocortin II (Cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-OH), opioid peptides (e.g. Met-Enkephalin (H-Tyr-Gly- Gly-Phe-Met-OH), Leu-Enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH), H-Tyr-D-Ala-Gly-N-Me-Phe-Met(O)-OL and H-Tyr-D-Ala-Gly-Phe-Leu-OH), neuropeptides, alkaloids, anti-inflammatory peptides, antimicrobial peptides (e.g., competence-stimulating peptides, tachyplesin, histatin peptides and their derivatives), calcium-binding peptides , regulatory peptides, peptide vaccines, and peptidomimetics (eg, α-helix mimetics and β-sheet mimetics).

In certain embodiments, the HPP or HPC transport unit comprises a protonatable amine group capable of facilitating or enhancing the transport or crossing of the HPP or HPC through one or more biological barriers. In certain embodiments, the protonatable amine group is substantially protonated at the pH of the biobarrier through which the HPP or HPC permeates. In certain embodiments, amine groups can be reversibly protonated or deprotonated.

In certain embodiments, the linker covalently links the functional unit to the HPP or HPC transport unit and comprises a bond that can be cleaved after the HPP or HPC permeates across one or more biological barriers. Cleavable bonds include, for example, covalent, ether, thioether, amide, ester, thioester, carbonate, carbamate, phosphate, or oxime bonds.

Another aspect of the invention relates to a pharmaceutical composition comprising at least one HPP or HPC of a peptide or peptide-related compound and a pharmaceutically acceptable carrier.

Another aspect of the invention relates to a method of penetrating biological barriers using a peptide or peptide-related compound HPP or HPC.

Another aspect of the invention relates to methods of diagnosing the onset, progression or remission of a condition in a biological subject by using HPP or HPC of a peptide or peptide-related compound. In certain embodiments, the HPP (or HPC) or functional units thereof are detectable. In certain embodiments, the HPP/HPC or functional units of HPP/HPC are uniquely detectable or labeled with or conjugated to a detectable marker.

Another aspect of the invention relates to methods of screening functional units, linkers or transport units for desired properties.

Another aspect of the invention relates to methods of preventing, ameliorating or treating a condition in a biological subject by administering a composition of the invention to the subject. In certain embodiments, the methods relate to treating a condition in a subject treatable with a peptide or peptide-related compound by administering a therapeutically effective amount of peptide HPP/HPC or a pharmaceutical composition thereof to the subject. In certain embodiments, conditions treatable by the methods include, but are not limited to, pain, trauma, inflammation-related conditions, microbial-related conditions, neuropeptide-related conditions, hormone-related conditions, tumors, abnormal blood pressure, Obesity, brain injury, allergies, male and female impotence, metastasis, and others, tuftsin, prepartum, postpartum, anti-AD activity, antidiuretic activity, calcium homeostasis, melanocytes, hormone release, platelets Conditions associated with aggregation, CNS activity, and phagocytosis are included.

In certain embodiments, the HPP/HPC pharmaceutical composition is an oral, enteral, buccal, intranasal, topical, rectal, intravaginal, aerosol, transmucosal, epidermal, transdermal It is administered to a living subject via a variety of routes including, but not limited to, cutaneous, intradermal, intraocular, intrapulmonary, subcutaneous and/or parenteral routes. In particularly preferred embodiments, pharmaceutical compositions of HPP are administered orally, transdermally, topically, subcutaneously and/or parenterally.

According to an advantage of the present invention, without intending to be limited to any particular mechanism, it is possible to locally administer a therapeutically effective amount of HPP or HPC to the site of a condition at high concentrations and low dosages. can. Advantages of the present invention include, for example, avoidance of systemic administration, reduced adverse effects (e.g., injection pain, gastrointestinal/rectal effects, and other side effects), and high localized HPP, HPC, or active agent. Potential novel therapeutics with concentrations are also mentioned. Advantages further include, for example, systemic administration of HPP or HPC to biological subjects to achieve faster and more efficient bioavailability, biological barriers that have been difficult to cross (e.g., the blood-brain barrier), and new adaptations as a result of crossing biobarriers.

structure 2, structure 3, structure 4, structure 5, structure 6, structure 7, structure 8, structure 9, structure 10, structure 11, structure 12, structure 13, structure 14, structure 15, structure 16, structure 17, structure 18 , Structure 19, Structure 20, Structure 21, Structure 22, Structure 23, Structure 24, Structure 25, Structure 26, Structure 27, Structure 28, Structure 37, Structure 38, Structure 39, Structure 40, Structure 41, Structure 42, Structure 43, structure 44, structure 45, structure 46, structure 47, structure 48, structure 49, structure 50, structure 51, structure 52, structure 53, structure 54, structure 55, structure 56, structure 57, structure 58, structure 59, structure 60, structure 61, structure 62, structure 63, structure 64, structure 65, structure 66, structure 67, structure 68, structure 69, structure 70, structure 71, structure 72, structure 73, structure 74, structure 75, structure 76 , Structure 77, Structure 78, Structure 79, Structure 80, Structure 81, Structure 82, Structure 83, Structure 84, Structure 85, Structure 86, Structure 87, Structure 88, Structure 89, Structure 90, Structure 91, Structure 92, Structure 93, structure 94, structure 95, structure 96, structure 97, structure 98, structure 99, structure 100, structure 101, structure 102, structure 103, structure 104, structure 105, structure 106, structure 107, structure 108, structure 109, Structure 110, Structure 111, Structure 112, Structure 113, Structure 114, Structure 115, Structure 116, Structure 117, Structure 118, Structure 119, Structure 120, Structure 121, Structure 122, Structure 123, Structure 124, Structure 125, Structure 126 , Structure 127, Structure 128, Structure 137, Structure 138, Structure 139, Structure 140, Structure 141, Structure 142, Structure 143, Structure 144, Structure 145, Structure 146, Structure 147, Structure 148, Structure 149, Structure 150, Structure 151, structure 152, structure 153, structure 154, structure 155, structure 156, structure 157, structure 158, structure 159, structure 160, structure 161, structure 162, structure 163, structure 164, structure 165, structure 166, structure 167, Structure 168, Structure 169, Structure 170, Structure 171, Structure 172, Structure 173, Structure 174, Structure 175, Structure 176, Structure 177, Structure 178, Structure 179, Structure 180, Structure 181, Structure 182, Structure 183, Structure 184 , structure 185, structure 186, structure 187, structure 188, structure 189, structure 190, structure 191, structure 192, structure 193, structure 194, structure 195, structure 196, structure 197, structure 198, structure 199, structure 200, structure 201, structure 202, structure 203, structure 204, structure 205, structure 206, structure 207, structure 208, structure 209, structure 210, structure 211, structure 212, structure 213, structure 214, structure 215, structure 216, structure 217 , structure 218, structure 219, structure 220, structure 221, structure 222, structure 223, structure 224, structure 225, structure 226, structure 227, structure 228, structure 237, structure 238, structure 239, structure 240, structure 241, structure 242, structure 243, structure 244, structure 245, structure 246, structure 247, structure 248, structure 249, structure 250, structure 251, structure 252, structure 253, structure 254, structure 255, structure 256, structure 257, structure 258, Structure 259, Structure 260, Structure 261, Structure 262, Structure 263, Structure 264, Structure 265, Structure 266, Structure 267, Structure 268, Structure 269, Structure 270, Structure 271, Structure 272, Structure 273, Structure 274, Structure 275 , structure 276, structure 277, structure 278, structure 279, structure 280, structure 281, structure 282, structure 283, structure 284, structure 285, structure 286, structure 287, structure 288, structure 289, structure 290, structure 291, structure 292, structure 293, structure 294, structure 295, structure 296, structure 297, structure 298, structure 299, structure 300, structure 301, structure 302, structure 303, structure 304, structure 305, structure 306, structure 307, structure 308, structure 309, structure 310, structure 311, structure 312, structure 313, structure 314, structure 315, structure 316, structure 317, structure 318, structure 319, structure 320, structure 321, structure 322, structure 323, structure 324, structure 325 , structure 326, structure 327, structure 328, structure 337, structure 338, structure 339, structure 340, structure 341, structure 342, structure 343, structure 344, and structure 345. FIG. Ac-Tyr(Ac)-Gly-Gly-Phe-Met-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ .HCl, HCl.() across isolated human skin tissue in Franz cells (n=5) _CH3 ) _{2NCH2CH2CH2CO -} Tyr ₍ Ac)-Gly _- Gly _- Phe _- Met _{- OCH2CH2CH2CH3} , cyclo(1,6)-Ac-Nle-Asp-His-Phe -Arg(diAc)-Trp-Lys-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ .HCl, cyclo(1,6)-H-Nle-Asp-His-D-Phe(4-I)-Arg (Ac)-Trp-Lys-NH ₂ ·HCl, Cyclo(1,6)-H-Nle-Asp-His-D-Ala(2-naphthyl)-Arg(NO ₂ )-Trp-Lys-NH ₂ · HCl, Ac-Val-Pro-Gly-Pro-Arg(diAc)-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ .HCl, Ac-Tyr-Gly-Gly-Phe-Met-OH, cyclo(1, 6) -Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-OH, cyclo(1,6)-Ac-Nle-Asp-His-D-Phe(4-I)-Arg-Trp-Lys Fig. 2 shows cumulative amounts of _-NH2 and H-Val-Pro-Gly-Pro-Arg-OH. In each case the vehicle was phosphate buffer (0.2 M) pH 7.4.

I. Structures of highly permeable prodrugs (HPPs) or highly permeable compositions (HPCs) of peptides or peptide-related compounds

One aspect of the present invention is directed to highly permeable prodrugs (HPPs) or highly permeable compositions (HPCs). The term "hyperpermeable prodrug" or "HPP" or "hyperpermeable composition" or "HPC" as used herein is a composition comprising a functional unit covalently linked via a linker to a transport unit point to things

The functional units of the HPP/HPC, including the portion of the parent drug, are desired to: 1) deliver the parent drug or HPP/HPC to a biological subject and/or transport the parent drug across a biobarrier; and 3) HPP/HPC have the property that they can be cleaved to convert portions of the parent drug to the parent drug or metabolites of the parent drug.

In certain embodiments, functional units may be hydrophilic, lipophilic or amphiphilic (ie, both hydrophilic and lipophilic). The lipophilic portion of the functional unit may be inherent or may be achieved by converting the hydrophilic portion of the functional unit into a lipophilic portion. For example, the lipophilic portion of the functional unit is created by converting one or more hydrophilic groups of the functional unit into lipophilic groups via organic synthesis. Examples of hydrophilic groups include, without limitation, carboxyl groups, hydroxyl groups, thiol groups, amine groups, phosphate/phosphonate groups and carbonyl groups. Lipophilic moieties created through modification of these hydrophilic groups include, without limitation, ethers, thioethers, esters, thioesters, carbonates, carbamates, amides, phosphates and oximes. In certain embodiments, functional units are lipophilized by acylation. In certain embodiments, functional units are lipophilized by esterification.

In certain embodiments, the HPP or HPC parent agent is selected from the group consisting of peptides and peptide-related compounds. Portions of peptides and peptide-related compounds can be further converted to lipophilic moieties as described above. As used herein, the term "peptide HPP/HPC" refers to HPP or HPC of peptides and peptide-related compounds. As used herein, the term "peptide HPPs/HPCs" refers to HPPs or HPCs of peptides and peptide-related compounds.

Peptides are well known in the art and are used in conjunction with various conditions. As used herein, a peptide refers to a sequence of amino acids, the sequence being from about 2 to about 50 amino acids in length. For example, peptides can be , 25, 26, 27, 28, 29, 30 or more amino acids. A peptide may contain both D-amino acids and/or L-amino acids.

Amino acids are compounds that contain both an amine and a carboxyl functional group. The carbon atom next to the carbonyl group of the carboxyl function is called the alpha carbon. An amino acid with a side chain attached to the alpha carbon is called an alpha amino acid. In amino acids having a carbon chain attached to the amino group and the alpha carbon, the carbons are labeled in the order alpha, beta, gamma, etc. from the carbonyl carbon. Amino acids with an amino group attached to the beta or gamma carbon are referred to as beta amino acids or gamma amino acids, respectively.

An alpha amino acid is an amino acid that has an amino group and a carboxyl group attached to the same carbon (the alpha carbon). The alpha carbon is one atom away from the carboxylic acid group. The alpha amino acid has structure 1:
_H2NCHR'COOH (Structure 1)
has the structure of
Including its stereoisomers and pharmaceutically acceptable salts thereof, wherein R' is a substituted and unsubstituted imidazolyl group, a substituted and unsubstituted cyanidino group, a substituted and unsubstituted carboxyl group, a substituted and unsubstituted carboxamide groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted alkylthio groups, substituted and unsubstituted substituted and unsubstituted alkylamino groups, substituted and unsubstituted alkylcarbonyl groups, substituted and unsubstituted perfluoroalkyl groups, substituted and unsubstituted alkyl halide groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heteroaryl selected from the group consisting of:

及びそれらの誘導体から成る群から選択される。 In certain embodiments, the amino acid has structure 1, including stereoisomers and pharmaceutically acceptable salts thereof, wherein R' is H—, CH ₃ , HN═C(NH ₂ )— NH—(CH ₂ ) ₃ —, H ₂ N—CO—CH ₂ —, HOOC—CH ₂ —, HS—CH ₂ —, H ₂ N—CO—(CH ₂ ) ₂ —, HS—(CH ₂ ) _2- , HOOC-( _CH2 ) _2- , _{CH3 - CH2 -} CH _{( CH3} )-, ( _CH3 )2CH-CH2-, _H2N- ( _CH2 ) _4- , CH3- S—(CH ₂ ) ₂ —, Phenyl-CH ₂ —, HO—CH ₂ —, CH ₃ —CH(OH)—, 4-OH-Phenyl-CH ₂ —, CH ₃ —CH(CH ₃ ),

and derivatives thereof.

Examples of alpha amino acids include, without limitation, alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamic acid (Glu), glutamine (Gln), glycine (Gly ), histidine (His), homocysteine (Hcy), homoserine (Hse), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), norleucine (Nle), norvaline (Nva), ornithine ( Orn), penicylamine (Pen), phenylalanine (Phe), proline (Pro), serine (Ser), tyrosine (Thr), threonine (Trp), tryptophan (Tyr), valine (Val), pyroglutamic acid (pGLU), dinitro benzylated lysine (dnp-LYS), phosphorylated threonine (pTHR), phosphorylated serine (pSER), phosphorylated tyrosine (pTYR), citrulline (CIT), N-methylated alanine (nme-ALA), N-methylation isoleucine (nme-ILE), N-methylated leucine (nme-LEU), N-methylated phenylalanine (nme-PHE), N-methylated valine (nme-VAL), N-methylated serine (nme-SER) , N-methylated threonine (nme-THR), N-methylated tyrosine (nme-TYR), alpha amino-butyric acid (alpha-ABA), isoaspartic acid (iso-ASP), acetylated lysine (Ac-LYS) , 2-methylalanine (2-Me-ALA), and oxamic acid (OXA).

A beta amino acid is an amino acid that has an amino group attached to the beta carbon that is the second most distant from the carboxylic acid group. Examples of beta amino acids include, without limitation, beta-alanine (β-Ala), beta-arginine (β-Arg), beta-asparagine (β-Asn), beta-aspartic acid (β-Asp), beta- Cysteine (β-Cys), Beta-Glutamic Acid (β-Glu), Beta-Glutamine (β-Gln), Beta-Histidine (β-His), Beta-Isoleucine (β-Ile), Beta-Leucine (β-Leu ), beta-lysine (β-Lys), beta-methionine (β-Met), beta-phenylalanine (β-Phe), beta-proline (β-Pro), beta-serine (β-Ser), beta-tyrosine (β-Thr), beta-threonine (β-Trp), beta-tryptophan (β-Tyr) and beta-valine (β-Val).

A gamma amino acid is an amino acid having an amino group attached to the gamma carbon that is the third furthest from the carboxylic acid group. Examples of gamma amino acids include, without limitation, gamma-glutamic acid (γ-GLU).

Peptide-related compounds are compounds that include peptide structures, peptide metabolites, or agents that can be metabolized to peptides or peptide metabolites after peptide HPP/HPC permeates one or more biological barriers. Peptide-related compounds are also peptides or peptide metabolite analogs or mimetics, or agents that can be metabolized to peptides or peptide metabolite analogs or mimetics after HPP or HPC permeates one or more biological barriers. Contains a compound.

Examples of peptides and peptide-related compounds include, but are not limited to, peptide hormones, neuropeptides, alkaloids, antimicrobial peptides, anti-inflammatory peptides, peptide toxins, regulatory peptides, calcium-binding peptides, peptide vaccines and peptidomimetics. not.

Peptide hormones are a class of peptides that have endocrine functions in living animals. Peptide hormones have also been identified in plants with important roles in intercellular communication and plant defense. Peptide hormones are released into a variety of organs and tissues such as heart (arterial-natriuretic peptide (ANP), arterial-natriuretic factor (ANF), pancreas (eg insulin, enterostatin, somatostatin), gastrointestinal tract (cholecystokinin , gastrin (eg gastrin-34, gastrin-17 and gastrin-14), opioid peptides (eg Met-enkephalin, Leu-enkephalin, H-Tyr-D-Ala-Gly-N-Me-Phe-Met(O )-OL and H-Tyr-D-Ala-Gly-Phe-Leu-OH), cholecystokinin, secretin, motilin, vasoactive intestinal peptide and enteroglucagon), adipose tissue stores (e.g. leptin), pituitary (e.g. luteinizing hormone, follicle stimulating hormone, prolactin, adrenocorticotropic hormone (ACTH), growth hormone, antidiuretic hormone, oxytocin, melanocortins (e.g. melanocortin II)), thyroid (e.g. calcitonin), spleen (e.g. , tuftsin), brain (e.g. oxytocin, dynorphin), liver (e.g. angiotensin, angiotensin I and angiotensin II), endothelium (e.g. endothelin) Other examples of peptide hormones include, but are not limited to: , thyroid stimulating hormone (TRH) and bradykinin.

Neuropeptides are peptides found in neural tissue that are involved in regulatory and signaling processes. Examples of neuropeptides include, but are not limited to, neurotransmitters (eg, N-acetylaspartylglutamate, gastrin, cholecystokinin, neuropeptide Y, vasopressin, oxytocin, secretin, substance P, somatostatin, vasoactive intestinal peptide (VIP), opioids (eg, enkephalins, dynorphins, endorphins), galatin, neurotensin, TRH, arterial-natriuretic peptide.

Alkaloids are usually peptides derived from plants, fungi and some animals such as shellfish. Alkaloids are involved in protecting one organism from consumption by the other organism. Examples of alkaloids include, but are not limited to, ergotamine, pandamine, dynorphin A-(1-8)-octapeptide, N-β-D-Leu-D-Arg-D-Arg-D-Leu-D-Phe )-naltrexamine.

Antimicrobial peptides are peptides that inhibit the growth of microorganisms such as bacterial cells, fungi and protozoa. Examples of antimicrobial peptides include, without limitation, bacitracin, gramicidin, valinomycin, competence-stimulating peptides, tachyplesin, histatin peptides and derivatives thereof.

Examples of anti-inflammatory peptides are peptides having the sequences SEQ ID NO: 47, SEQ ID NO: 48 and SEQ ID NO: 49 (Table A).

Peptide toxins are peptides that are toxic. Examples of peptide toxins are partoxin, agatoxin and cartatoxin.

A regulatory peptide is a peptide that modulates one or more processes in a biological subject. Examples of regulatory peptides include, without limitation, anserine and carmosine.

Other examples of peptides and peptide-related compounds include calcium-binding peptides, peptide vaccines [p45 (IEIGLEGKGFEPTLE ALFGK) and p210 (KTTKQSFDLS VKAQY KKNKH)] and peptidomimetics (e.g., α-helix and β-sheet mimetics). ).

構造Ｆ－１
の構造を有する部分を含み、その立体異性体及び薬学上許容可能なその塩を含み、式中、 各Ａ₁～Ａ_mは独立して２－ナフチルアラニン、置換及び非置換のアルキル、置換及び非置換のシクロアルキル、置換及び非置換のヘテロシクロアルキル、置換及び非置換のアルコキシ、置換及び非置換のアルケニル、置換及び非置換のアルキニル、置換及び非置換のアリール、置換及び非置換のヘテロアリールの残基、及び構造Ａ：

構造Ａ
から成る群から選択され；
Ａ₁～Ａ_mのｐは独立して選択される整数であり；
各Ａ₁～Ａ_m、Ｚ_NT、Ｚ_CT-1及びＺ_CT-2についての各Ａ₁～Ａ_mの各炭素におけるＺ_A-1は独立して、Ｈ、ＣＨ₃、Ｃ₂Ｈ_5、Ｃ₃Ｈ₇、ＣＦ₃、Ｃ₂Ｆ₅、Ｃ₃Ｆ₇、置換及び非置換のアルキル、置換及び非置換のパーフルオロアルキル、並びに置換及び非置換のアルキルハライドから成る群から選択され；
各Ａ₁～Ａ_m、Ｒ_NT及びＲ_CTの各炭素におけるＲ_Aは、Ｈ、置換及び非置換のイミダゾリル、置換及び非置換のグアニジノ、置換及び非置換のカルボキシル、置換及び非置換のカルボキサミド、置換及び非置換のアルキル、置換及び非置換のシクロアルキル、置換及び非置換のヘテロシクロアルキル、置換及び非置換のアルコキシ、置換及び非置換のアルキルチオ、置換及び非置換のアルキルアミノ、置換及び非置換のアルキルカルボニル、置換及び非置換のパーフルオロアルキル、置換及び非置換のアルキルハライド、置換及び非置換のアリール、並びに置換及び非置換のヘテロアリールの基から成る群から選択され；
Ａ₁～Ａ_mのｐが２未満の整数である場合、各炭素上のＲ_Aは、同一であっても、異なっていてもよく、各炭素上のＺ_A-1は同一であっても、異なっていてもよく；
ペプチド鎖におけるアミノ官能基及びカルボキシ官能基はさらにラクタム架橋を形成してもよく；
チオール基はさらにジスルフィド架橋を形成してもよい。 In a particular embodiment, the functional unit of peptide HPP/HPC has structure F-1

Structure F-1
and including stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein each A ₁ -A _m is independently 2-naphthylalanine, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl and structure A:

Structure A
selected from the group consisting of;
p in A ₁ -A _m is an independently selected integer;
Z _A-1 at each carbon of each A ₁ -A _m for each A ₁ -A _m , Z _NT , Z _CT-1 and Z _CT-2 is independently H, CH ₃ , C ₂ H _{5 ,} selected from the group consisting of _C3H7 , _CF3 , _{C2F5 , C3F7} , substituted and _{unsubstituted} alkyl, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide _;
R _A at each carbon of each A ₁ to A _m , R _NT and R _CT is H, substituted and unsubstituted imidazolyl, substituted and unsubstituted guanidino, substituted and unsubstituted carboxyl, substituted and unsubstituted carboxamide, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl groups;
When p in A ₁ to A _m is an integer less than 2, R _A on each carbon may be the same or different, and Z _A-1 on each carbon may be the same. , which may be different;
Amino and carboxy functional groups in the peptide chain may further form lactam bridges;
Thiol groups may also form disulfide bridges.

In certain embodiments, the peptide HPP/HPC functional unit comprises a moiety having a structure selected from the group consisting of structure F-1 as defined above, stereoisomers thereof and pharmaceutically acceptable Including salts thereof, wherein R _A of A ₁ -A _m may be further lipophilized by acylation or esterification.

In certain embodiments, the peptide HPP/HPC functional unit comprises a moiety having a structure selected from the group consisting of structure F-1 as defined above, stereoisomers thereof and pharmaceutically acceptable and m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 .

In certain embodiments, the peptide HPP/HPC functional unit comprises a moiety having structure F-1 as defined above, including stereoisomers and pharmaceutically acceptable salts thereof, wherein p is 1, 2 or 3;

In certain embodiments, the peptide HPP/HPC functional unit comprises a moiety having structure F-1 as defined above, including stereoisomers and pharmaceutically acceptable salts thereof, wherein
p is 1, 2 or 3;
Z _A-1 at each carbon of each A ₁ to A _m and Z _A-2 for each A ₁ to A _m , Z _NT , Z _CT-1 and Z _CT-2 is independently H, CH ₃ , the group consisting of _{C2H5 , C3H7} , _CF3 , _{C2F5 , C3F7} , substituted and _{unsubstituted} alkyl, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide _; selected from;
R _A at each carbon of each A ₁ to A _m , R _NT and R _CT is H, substituted and unsubstituted imidazolyl, substituted and unsubstituted guanidino, substituted and unsubstituted carboxyl, substituted and unsubstituted carboxamide, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl groups;
When p in A ₁ to A _m is an integer less than 2, R _A on each carbon may be the same or different, and Z _A-1 on each carbon may be the same. , which may be different;
Amino and carboxy functional groups in the peptide chain may further form lactam bridges;
Thiol groups may also form disulfide bridges.

As used herein, the term "pharmaceutically acceptable salts" means salts of the compounds of the invention that are safe for application in subjects. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the compounds of the invention. Pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetic acid Salt, Lactate, Salicylate, Citrate, Tartrate, Pantothenate, Bitartrate, Ascorbate, Succinate, Maleate, Genistate, Fumarate, Gluconate, Glucaronate , saccharates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates (i.e., 1,11-methylene- Suitable base salts include, but are not limited to, bis-(3-hydroxy-3-naphthoate) Certain compounds of the present invention are capable of forming pharmaceutically acceptable salts with various amino acids. include, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts and diethanolamine salts For a general description of pharmaceutically acceptable salts, see this reference. See BERGE et al., 66 J. PHARM.SCI.1-19 (1977), incorporated herein.

As used herein, unless otherwise specified, the term “alkyl” means a branched or unbranched, saturated or unsaturated, monovalent or polyvalent hydrocarbon group, including saturated including alkyl, alkenyl and alkynyl groups. Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, Heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, decynyl, undecenyl, dodecynyl, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, t-butylene , pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, and dodecylene. In certain embodiments, the hydrocarbon group contains 1-30 carbons. In certain embodiments, the hydrocarbon group contains 1-20 carbons. In certain embodiments, the hydrocarbon group contains 1-12 carbons.

As used herein, unless otherwise specified, the term "cycloalkyl" means an alkyl containing at least one ring and no aromatic rings. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In certain embodiments, the hydrocarbon chain contains 1-30 carbons. In certain embodiments, the hydrocarbon group contains 1-20 carbons. In certain embodiments, the hydrocarbon group contains 1-12 carbons.

As used herein, unless otherwise specified, the term "heterocycloalkyl" means a cycloalkyl in which at least one of the ring atoms is a non-carbon atom. Examples of non-carbon ring atoms include, but are not limited to, S, O and N.

As used herein, unless otherwise specified, the term "alkoxy" means an alkyl, cycloalkyl or heterocycloalkyl containing one or more oxygen atoms. Examples of alkoxy include, but are not limited to, -CH ₂ -OH, -OCH ₃ , -O-alkyl, -alkyl-OH, -alkyl-O-alkyl-, wherein two alkyl can be the same or can be different.

As used herein, unless otherwise specified, the term "alkylhalide" means an alkyl, cycloalkyl or heterocycloalkyl containing one or more halogen atoms, wherein the halogen atoms are identical can be, or can be different. The term "halogen" means fluorine, chlorine, bromine or iodine. Examples of alkyl halides include -alkyl-F, -alkyl-Cl, -alkyl-Br, -alkyl-I, -alkyl(F)-, -alkyl(Cl)-, -alkyl(Br)-, and - Alkyl(I)— includes, but is not limited to.

As used herein, unless otherwise specified, the term "alkylthio" means an alkyl, cycloalkyl or heterocycloalkyl containing one or more sulfur atoms. Examples of alkylthio include, but are not limited to, -CH ₂ -SH, -SCH ₃ , -S-alkyl, -alkyl-SH, -alkyl-S-alkyl-, wherein two alkyl can be the same or can be different.

As used herein, unless otherwise specified, the term "alkylamino" means an alkyl, cycloalkyl or heterocycloalkyl containing one or more nitrogen atoms. Examples of alkylamino include -CH ₂ -NH, -NCH ₃ , -N(alkyl)-alkyl-, N-alkyl-, -alkyl-NH ₂ , -alkyl-N-alkyl- and -alkyl-N( include, but are not limited to, alkyl)-alkyl-, wherein the alkyls can be the same or different.

As used herein, unless otherwise specified, the term "alkylcarbonyl" means an alkyl, cycloalkyl or heterocycloalkyl containing one or more carbonyl groups. Examples of alkylcarbonyl groups include aldehyde groups (-R-C(O)-H), ketone groups (-R-C(O)-R'), carboxylic acid groups (R-COOH), ester groups (- R-COO-R'), carboxamide (-R-COO-N(R')R''), enone group (-RC(O)-C(R')=C(R'')R' ''), acyl halide groups (--R--C(O)--X) and acid anhydride groups (---R--C(O)--O--C(O)--R'). , wherein R, R′, R″ and R′″ are the same or different alkyl, cycloalkyl or heterocycloalkyl.

As used herein, unless otherwise specified, the term "perfluoroalkyl" means an alkyl, cycloalkyl or heterocycloalkyl containing one or more fluoro groups, including but not limited to perfluoromethyl , perfluoroethyl and perfluoropropyl.

As used herein, unless otherwise specified, the term "aryl" means chemical structures containing one or more aromatic rings. In certain embodiments, the ring atoms are all carbon. In certain embodiments, one or more ring atoms are non-carbon, eg, oxygen, nitrogen, or sulfur (“heteroaryl”). Examples of aryl include, without limitation, phenyl, benzyl, naphthalenyl, anthracenyl, pyridyl, quinolyl, isoquinolyl, pyrazinyl, quinoxalinyl, acridinyl, pyrimidinyl, quinazolinyl, pyridazinyl, cinnolinyl, imidazolyl, benzimidazolyl, purinyl, indolyl, furanyl, benzofuranyl. , isobenzofuranyl, pyrrolyl, indolyl, isoindolyl, thiophenyl, benzothiophenyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, thiaxolyl, quanidide and benzothiazolyl.

In certain embodiments, the HPP/HPC transport unit facilitates transport or crossing of HPP/HPC through one or more biological barriers (e.g., > about 10-fold, > about 50-fold, > about 100 times, > about 300 times, > about 500 times, > about 1000 times faster). In certain embodiments, the protonatable amine group is substantially protonated at physiological pH. In certain embodiments, amine groups are reversibly protonated. In certain embodiments, the transport unit may or may not be cleaved from the functional unit after penetration of HPP/HPC through one or more biological barriers. In certain embodiments, the transport unit may be derived from a functional unit, particularly for peptides or peptide-related compounds having at least a free amino group. In certain embodiments, when a peptide or peptide-related compound has more than one protonatable group, the peptide or peptide-related compound is left with one or two protonatable amine groups and the other protonatable All groups are modified to be protected.

In certain embodiments, the protonatable amine groups are pharmaceutically acceptable substituted and unsubstituted primary amine groups, pharmaceutically acceptable substituted and unsubstituted secondary amine groups, and pharmaceutically acceptable is selected from the group consisting of substituted and unsubstituted tertiary amine groups;

構造Ｎｒ
その立体異性体及び薬学上許容可能なその塩を含む。 In certain embodiments, the protonatable amine group has structure Na, structure Nb, structure Nc, structure Nd, structure Ne, structure Nf, structure Ng, structure Nh, structure Ni, structure Nj, structure Nk, structure Nl, is selected from the group consisting of Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr:

Structure Nr
Including its stereoisomers and pharmaceutically acceptable salts thereof.

As used herein, unless otherwise specified, each R ₁₁ -R ₁₆ is independently none, H, CH ₂ COOR ₁₁ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted selected from the group consisting of perfluoroalkyl, substituted and unsubstituted alkyl halides, wherein carbon or hydrogen is further independently replaced by O, S, P, NR ₁₁ or other pharmaceutically acceptable groups; may

In certain embodiments, the linker covalently joining the HPP/HPC functional unit and the transport unit comprises a bond that can be cleaved after penetration of the HPP/HPC across one or more BBs. Cleavable bonds include, for example, covalent bonds, ether bonds, thioether bonds, amide bonds, ester bonds, thioester bonds, carbonate bonds, carbamate bonds, phosphate bonds, or oxime bonds.

構造Ｌ－１
を有し、
その立体異性体及び薬学上許容可能なその塩を含み、式中、
Ｆは、ペプチドＨＰＰ／ＨＰＣの機能ユニットである。Ｆの例には上記で定義された構造Ｆ－１が挙げられ；
Ｔ_C及びＴ_Nは独立して、無、Ｈ，置換及び非置換のアルキル基、置換及び非置換のシクロアルキル基、置換及び非置換のヘテロシクロアルキル基、置換及び非置換のアルキルオキシ基、置換及び非置換のアルケニル基、置換及び非置換のアルキニル基、置換及び非置換のアリール基、置換及び非置換のヘテロアリール基、上記で定義されたような構造Ｎａ，構造Ｎｂ，構造Ｎｃ，構造Ｎｄ，構造Ｎｅ，構造Ｎｆ，構造Ｎｇ，構造Ｎｈ，構造Ｎｉ，構造Ｎｊ，構造Ｎｋ，構造Ｎｌ，構造Ｎｍ，構造Ｎｎ，構造Ｎｏ，構造Ｎｐ，構造Ｎｑ，及び構造Ｎｒから成る群から選択され：
Ｌ_1C及びＬ_1Nは独立して、無、Ｏ、Ｓ、Ｎ（Ｌ₃）、－Ｎ（Ｌ₃）－ＣＨ₂－Ｏ、－Ｎ（Ｌ₃）－ＣＨ₂－Ｎ（Ｌ₅）－、－Ｏ－ＣＨ₂－Ｏ－、－Ｏ－ＣＨ（Ｌ₃）－Ｏ及び－Ｓ－ＣＨ（Ｌ₃）－Ｏ－から成る群から選択され；
Ｌ_2C及びＬ_2Nは独立して、無、Ｏ、Ｓ、Ｎ（Ｌ₃）、－Ｎ（Ｌ₃）－ＣＨ₂－Ｏ、－Ｎ（Ｌ₃）－ＣＨ₂－Ｎ（Ｌ₅）－、－Ｏ－ＣＨ₂－Ｏ－、－Ｏ－ＣＨ（Ｌ₃）－Ｏ、－Ｓ－ＣＨ（Ｌ₃）－Ｏ－、－Ｏ－Ｌ₃－、－Ｎ－Ｌ₃－、－Ｓ－Ｌ₃－、－Ｎ（Ｌ₃）－Ｌ₅－及びＬ₃から成る群から選択され：

Ｌ_4C及びＬ_4Nは独立して、無、Ｃ＝Ｏ、Ｃ＝Ｓ、

及び

から成る群から選択され；
各Ｌ_1C、Ｌ_1N、Ｌ_2C、Ｌ_2N、Ｌ_4C及びＬ_4Nについて、Ｌ₃及びＬ₅は独立して、無、Ｈ、ＣＨ₂ＣＯＯＬ₆、置換及び非置換のアルキル基、置換及び非置換のシクロアルキル基、置換及び非置換のヘテロシクロアルキル基、置換及び非置換のアリール、置換及び非置換のヘテロアリール、置換及び非置換のアルコキシ、置換及び非置換のアルキルチオ、置換及び非置換のアルキルアミノ、置換及び非置換のパーフルオロアルキル、置換及び非置換のアルキルハライドから成る群から選択され、その際、炭素又は水素はさらに独立して、Ｏ、Ｓ、Ｐ、ＮＬ₃又はそのほかの薬学上許容可能な基によって置き換えられてもよく；
Ｌ₆は独立してＨ、ＯＨ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、置換及び非置換のアルキル基、置換及び非置換のシクロアルキル基、置換及び非置換のヘテロシクロアルキル基、置換及び非置換のアリール、置換及び非置換のヘテロアリール、置換及び非置換のアルコキシ、置換及び非置換のアルキルチオ、置換及び非置換のアルキルアミノ、置換及び非置換のパーフルオロアルキル、置換及び非置換のアルキルハライドから成る群から選択され、その際、炭素又は水素はさらに独立して、Ｏ、Ｓ、Ｎ、Ｐ（Ｏ）ＯＬ₆、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＬ₆、ＣＬ₆Ｌ₇、アリール、ヘテロアリール又は環状の基によって置き換えられてもよく；
Ｌ₇は独立してＨ、ＯＨ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、置換及び非置換のアルキル基、置換及び非置換のシクロアルキル基、置換及び非置換のヘテロシクロアルキル基、置換及び非置換のアリール、置換及び非置換のヘテロアリール、置換及び非置換のアルコキシ、置換及び非置換のアルキルチオ、置換及び非置換のアルキルアミノ、置換及び非置換のパーフルオロアルキル、置換及び非置換のアルキルハライドから成る群から選択され、その際、炭素又は水素はさらに独立して、Ｏ、Ｓ、Ｎ、Ｐ（Ｏ）ＯＬ₆、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＬ₆、ＣＬ₆Ｌ₇、アリール、ヘテロアリール又は環状の基によって置き換えられてもよい。 In certain embodiments, the peptide HHP/HPC has the following structure L-1:

Structure L-1
has
including stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein
F is a functional unit of peptide HPP/HPC. Examples of F include structure F-1 defined above;
T _C and T _N are independently nothing, H, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkyloxy groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heteroaryl groups, structure Na as defined above, structure Nb, structure Nc, structure Nd, structure Ne, structure Nf, structure Ng, structure Nh, structure Ni, structure Nj, structure Nk, structure Nl, structure Nm, structure Nn, structure No, structure Np, structure Nq, and structure Nr. :
L _1C and L _1N are independently none, O, S, N(L ₃ ), —N(L ₃ )—CH ₂ —O, —N(L ₃ )—CH ₂ —N(L ₅ )— , —O—CH ₂ —O—, —O—CH(L ₃ )—O and —S—CH(L ₃ )—O—;
L _2C and L _2N are independently none, O, S, N(L ₃ ), —N(L ₃ )—CH ₂ —O, —N(L ₃ )—CH ₂ —N(L ₅ )— , -O-CH ₂ -O-, -O-CH(L ₃ )-O, -S-CH(L ₃ )-O-, -OL _{3 -, -N-L 3 -} , -S- selected from the group consisting of L ₃ -, -N(L ₃ )-L ₅ - and L ₃ :

L _4C and L _4N are independently none, C=O, C=S,

as well as

selected from the group consisting of;
For each L _1C , L _1N , L _2C , L _2N , L _4C and L _4N , L ₃ and L ₅ are independently none, H, CH ₂ COOL ₆ , substituted and unsubstituted alkyl groups, substituted and unsubstituted substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted selected from the group consisting of alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halides, wherein carbon or hydrogen is further independently O, S, P _, NL3 or other may be replaced by upper-acceptable groups;
L ₆ is independently H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted consisting of aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide is selected from the group wherein carbon or hydrogen is further independently O, S, N, P(O) _OL6 , CH=CH, C[ _identical to]C, _CHL6 , _CL6L7 , aryl, heteroaryl or may be replaced by a cyclic group;
L ₇ is independently H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted consisting of aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide is selected from the group wherein carbon or hydrogen is further independently O, S, N, P(O) _OL6 , CH=CH, C[ _identical to]C, _CHL6 , _CL6L7 , aryl, heteroaryl or may be replaced by a cyclic group.

In certain embodiments, the peptide or peptide-related compound HPP or HPC comprises the structure of structure L-1, including stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein F, L _1C , L _1N , _{L2C, L2N , TC} and _TN are as defined above, and _L4C and/or _L4N are C=O.

In certain embodiments, the peptide or peptide-related compound HPP or HPC comprises the structure of structure L-1, including stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein:
F, L _1C , L _1N , L _2C , L _2N , L _4C and L _4N are as defined above;
T _C is the transport unit of the peptide HPP/HPC. For example, T _C can be structure Na, structure Nb, structure Nc, structure Nd, structure Ne, structure Nf, structure Ng, structure Nh, structure Ni, structure Nj, structure Nk, structure Nl, structure is selected from the group consisting of Nm, structure Nn, structure No, structure Np, structure Nq, and structure Nr:
T _N is none, H, substituted and unsubstituted alkyl group, substituted and unsubstituted cycloalkyl group, substituted and unsubstituted heterocycloalkyl group, substituted and unsubstituted alkyloxy group, substituted and unsubstituted alkenyl substituted and unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heteroaryl groups.

In certain embodiments, the peptide or peptide-related compound HPP or HPC comprises the structure of structure L-1, including stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein:
F, L _1C , L _1N , L _2C , L _2N , L _4C and L _4N are as defined above;
_TN is the transport unit of the peptide HPP/HPC. For example, T _N is structure Na, structure Nb, structure Nc, structure Nd, structure Ne, structure Nf, structure Ng, structure Nh, structure Ni, structure Nj, structure Nk, structure Nl, structure is selected from the group consisting of Nm, structure Nn, structure No, structure Np, structure Nq, and structure Nr:
T _C is none, H, substituted and unsubstituted alkyl group, substituted and unsubstituted cycloalkyl group, substituted and unsubstituted heterocycloalkyl group, substituted and unsubstituted alkyloxy group, substituted and unsubstituted alkenyl substituted and unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heteroaryl groups.

構造Ｌ－２
を有し、その立体異性体及び薬学上許容可能なその塩を含み、式中、
各Ａ₁～Ａ_mは独立して、２－ナフチルアラニン、置換及び非置換のアルキル、置換及び非置換のシクロアルキル、置換及び非置換のヘテロシクロアルキル、置換及び非置換のアルコキシ、置換及び非置換のアルケニル、置換及び非置換のアルキニル、置換及び非置換のアリール、置換及び非置換のヘテロアリールの残基、構造Ａ及び構造Ｂ：

構造Ａ

構造Ｂ
から成る群から選択され；
Ａ₁～Ａ_mのｐは独立して選択される整数であり；
各Ａ₁～Ａ_m及びＴ_NのＴ_Bは独立して、無、Ｈ、置換及び非置換のアルキル、置換及び非置換のシクロアルキル、置換及び非置換のヘテロシクロアルキル、置換及び非置換のアルキルオキシ、置換及び非置換のアルケニル、置換及び非置換のアルキニル、置換及び非置換のアリール、置換及び非置換のヘテロアリール、上記で定義されたような構造Ｎａ，構造Ｎｂ，構造Ｎｃ，構造Ｎｄ，構造Ｎｅ，構造Ｎｆ，構造Ｎｇ，構造Ｎｈ，構造Ｎｉ，構造Ｎｊ，構造Ｎｋ，構造Ｎｌ，構造Ｎｍ，構造Ｎｎ，構造Ｎｏ，構造Ｎｐ，構造Ｎｑ，及び構造Ｎｒから成る群から選択され：
各Ａ₁～Ａ_m、Ｌ_1C及びＬ_1NのＬ_1Bは独立して、無、Ｏ、Ｓ、－Ｎ（Ｌ₃）－、－Ｎ（Ｌ₃）－ＣＨ₂－Ｏ、－Ｎ（Ｌ₃）－ＣＨ₂－Ｎ（Ｌ₅）－、－Ｏ－ＣＨ₂－Ｏ－、－Ｏ－ＣＨ（Ｌ₃）－Ｏ及び－Ｓ－ＣＨ（Ｌ₃）－Ｏ－から成る群から選択され：
各Ａ₁～Ａ_m、Ｌ_2C及びＬ_2NのＬ_2Bは独立して、無、Ｏ、Ｓ、－Ｎ（Ｌ₃）－、－Ｎ（Ｌ₃）－ＣＨ₂－Ｏ、－Ｎ（Ｌ₃）－ＣＨ₂－Ｎ（Ｌ₅）－、－Ｏ－ＣＨ₂－Ｏ－、－Ｏ－ＣＨ（Ｌ₃）－Ｏ、－Ｓ－ＣＨ（Ｌ₃）－Ｏ－、－Ｏ－Ｌ₃－、－Ｎ－Ｌ₃－、－Ｓ－Ｌ₃－及び－Ｎ（Ｌ₃）－Ｌ₅－から成る群から選択され：
各Ａ₁～Ａ_mのＬ_4B、Ｌ_4C及びＬ_4Nは、Ｃ＝Ｏ、Ｃ＝Ｓ、

及び

から成る群から選択され：
Ｌ₃及びＬ₅は上記で定義されたとおりであり；
各Ａ₁－Ａ_m、Ｚ_NT、Ｚ_CT-1及びＺ_CT-2についてのＡ₁－Ａ_m、Ｚ_A-2の各炭素におけるＺ_A-1は独立して、Ｈ、ＣＨ₃、Ｃ₂Ｈ_5、Ｃ₃Ｈ₇、ＣＦ₃、Ｃ₂Ｆ₅、Ｃ₃Ｆ₇、置換及び非置換のアルキル、置換及び非置換のパーフルオロアルキル、並びに置換及び非置換のアルキルハライドから成る群から選択され；
各Ａ₁～Ａ_m、Ｒ_NT及びＲ_CTの各炭素における各Ａ₁～Ａ_m、Ｒ_Bの各炭素上のＲ_Aは独立して、置換及び非置換のイミダゾリル基、置換及び非置換のキアニジノ基、置換及び非置換のカルボキシル基、置換及び非置換のカルボキサミド基、置換及び非置換のアルキル基、置換及び非置換のシクロアルキル基、置換及び非置換のヘテロシクロアルキル基、置換及び非置換のアルコキシ基、置換及び非置換のアルキルチオ基、置換及び非置換のアルキルアミノ基、置換及び非置換のアルキルカルボニル基、置換及び非置換のパーフルオロアルキル基、置換及び非置換のアルキルハライド基、置換及び非置換のアリール基、並びに置換及び非置換のヘテロアリール基から成る群から選択され；
Ａ₁～Ａ_mのｐが２未満の整数である場合、各炭素上のＲ_A又はＲ_Bは、同一であっても、異なっていてもよく、各炭素上のＺ_A-1は同一であっても、異なっていてもよく；
ペプチド鎖におけるアミノ官能基及びカルボキシ官能基はさらにラクタム架橋を形成してもよく；
チオール基はさらにジスルフィド架橋を形成してもよい。
ペプチドＨＰＰｓ／ＨＰＣｓの例 In certain embodiments, the peptide HPP/HPC has the following structure L-2:

Structure L-2
having the formula, including stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein:
Each A ₁ -A _m is independently 2-naphthylalanine, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted Substituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl residues, structure A and structure B:

Structure A

Structure B
selected from the group consisting of;
p in A ₁ -A _m is an independently selected integer;
T _B of each A ₁ to A _m and T _N independently represents none, H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted Alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, structure Na, structure Nb, structure Nc, structure Nd as defined above. , structure Ne, structure Nf, structure Ng, structure Nh, structure Ni, structure Nj, structure Nk, structure Nl, structure Nm, structure Nn, structure No, structure Np, structure Nq, and structure Nr:
L _1B of each A ₁ to A _m , L _1C and L _1N is independently none, O, S, -N(L ₃ )-, -N(L ₃ )-CH ₂ -O, -N(L ₃ ) selected from the group consisting of -CH ₂ -N(L ₅ )-, -O-CH ₂ -O-, -O-CH(L ₃ )-O and -S-CH(L ₃ )-O- :
L _2B of each A ₁ to A _m , L _2C and L _2N is independently none, O, S, -N(L ₃ )-, -N(L ₃ )-CH ₂ -O, -N(L ₃ ) —CH ₂ —N(L ₅ )—, —O—CH ₂ —O—, —O—CH(L ₃ )—O, —S—CH(L ₃ )—O—, —OL ₃ is selected from the group consisting of -, -NL ₃ -, -SL ₃ - and -N(L ₃ )-L ₅ -:
L _4B , L _4C and L _4N of each A ₁ to A _m are C=O, C=S,

as well as

is selected from the group consisting of:
L3 and _{L5 are} as defined above;
Z _A-1 at each carbon of A ₁ -A _m and Z _A-2 for each A ₁ -A _m , Z _NT, Z _CT-1 and Z _CT-2 is independently H, CH ₃ , C from the group consisting of _2H5 , _C3H7 , _CF3 , _{C2F5 , C3F7 ,} substituted and _{unsubstituted} alkyl, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted alkyl halide _; selected;
R A on each carbon of A ₁ to A _m and R _B in each carbon of A ₁ to _{A m} , R _NT and R _CT are independently substituted and unsubstituted imidazolyl groups, substituted and unsubstituted cyanidino group, substituted and unsubstituted carboxyl group, substituted and unsubstituted carboxamide group, substituted and unsubstituted alkyl group, substituted and unsubstituted cycloalkyl group, substituted and unsubstituted heterocycloalkyl group, substituted and unsubstituted alkoxy group, substituted and unsubstituted alkylthio group, substituted and unsubstituted alkylamino group, substituted and unsubstituted alkylcarbonyl group, substituted and unsubstituted perfluoroalkyl group, substituted and unsubstituted alkyl halide group, substituted and unsubstituted aryl groups, and substituted and unsubstituted heteroaryl groups;
When p in A ₁ to A _m is an integer less than 2, R _A or R _B on each carbon may be the same or different, and Z _A-1 on each carbon is the same may be one or the other;
Amino and carboxy functional groups in the peptide chain may further form lactam bridges;
Thiol groups may also form disulfide bridges.
Examples of peptide HPPs/HPCs

In certain embodiments, the peptide HPP/HPC has structure 2, structure 3, structure 4, structure 5, structure 6, structure 7, structure 8, structure 9, structure 10, structure 11, structure 12, Structure 13, Structure 14, Structure 15, Structure 16, Structure 17, Structure 18, Structure 19, Structure 20, Structure 21, Structure 22, Structure 23, Structure 24, Structure 25, Structure 26, Structure 27, Structure 28, structure 37, structure 38, structure 39, structure 40, structure 41, structure 42, structure 43, structure 44, structure 45, structure 46, structure 47, structure 48, structure 49, structure 50, structure 51, structure 52, structure 53 , Structure 54, Structure 55, Structure 56, Structure 57, Structure 58, Structure 59, Structure 60, Structure 61, Structure 62, Structure 63, Structure 64, Structure 65, Structure 66, Structure 67, Structure 68, Structure 69, Structure 70, structure 71, structure 72, structure 73, structure 74, structure 75, structure 76, structure 77, structure 78, structure 79, structure 80, structure 81, structure 82, structure 83, structure 84, structure 85, structure 86, structure 87, structure 88, structure 89, structure 90, structure 91, structure 92, structure 93, structure 94, structure 95, structure 96, structure 97, structure 98, structure 99, structure 100, structure 101, structure 102, structure 103 , structure 104, structure 105, structure 106, structure 107, structure 108, structure 109, structure 110, structure 111, structure 112, structure 113, structure 114, structure 115, structure 116, structure 117, structure 118, structure 119, structure 120, structure 121, structure 122, structure 123, structure 124, structure 125, structure 126, structure 127, structure 128, structure 137, structure 138, structure 139, structure 140, structure 141, structure 142, structure 143, structure 144, Structure 145, Structure 146, Structure 147, Structure 148, Structure 149, Structure 150, Structure 151, Structure 152, Structure 153, Structure 154, Structure 155, Structure 156, Structure 157, Structure 158, Structure 159, Structure 160, Structure 161 , structure 162, structure 163, structure 164, structure 165, structure 166, structure 167, structure 168, structure 169, structure 170, structure 171, structure 172, structure 173, structure 174, structure 175, structure 176, structure 177, structure 178, structure 179, structure 180, structure 181, structure 182, structure 183, structure 184, structure 185, structure 186, structure 187, structure 188, structure 189, structure 190, structure 191, structure 192, structure 193, structure 194, Structure 1 95, Structure 196, Structure 197, Structure 198, Structure 199, Structure 200, Structure 201, Structure 202, Structure 203, Structure 204, Structure 205, Structure 206, Structure 207, Structure 208, Structure 209, Structure 210, Structure 211, structure 212, structure 213, structure 214, structure 215, structure 216, structure 217, structure 218, structure 219, structure 220, structure 221, structure 222, structure 223, structure 224, structure 225, structure 226, structure 227, structure 228 , Structure 237, Structure 238, Structure 239, Structure 240, Structure 241, Structure 242, Structure 243, Structure 244, Structure 245, Structure 246, Structure 247, Structure 248, Structure 249, Structure 250, Structure 251, Structure 252, Structure 253, structure 254, structure 255, structure 256, structure 257, structure 258, structure 259, structure 260, structure 261, structure 262, structure 263, structure 264, structure 265, structure 266, structure 267, structure 268, structure 269, Structure 270, Structure 271, Structure 272, Structure 273, Structure 274, Structure 275, Structure 276, Structure 277, Structure 278, Structure 279, Structure 280, Structure 281, Structure 282, Structure 283, Structure 284, Structure 285, Structure 286 , Structure 287, Structure 288, Structure 289, Structure 290, Structure 291, Structure 292, Structure 293, Structure 294, Structure 295, Structure 296, Structure 297, Structure 298, Structure 299, Structure 300, Structure 301, Structure 302, Structure 303, structure 304, structure 305, structure 306, structure 307, structure 308, structure 309, structure 310, structure 311, structure 312, structure 313, structure 314, structure 315, structure 316, structure 317, structure 318, structure 319, Structure 320, Structure 321, Structure 322, Structure 323, Structure 324, Structure 325, Structure 326, Structure 327, Structure 328, Structure 337, Structure 338, Structure 339, Structure 340, Structure 341, Structure 342, Structure 343, Structure 344 and structure 345, including stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein:
R is H, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues of
_X , _X4 , _X5 , X6, _X7 , _X8 , _X9 , _X10 , _X21 , _X22 , _X23 , _X24 , _X25 , _X26 and _X27 are independently C= O, C=S, COO, CSO, CH2OCO, COOCH2OCO, _COCH2OCO , _{CH2 -} O-CH( _CH2OR4 ) ₂ , _{CH2 -} O _- CH _{( CH2OCOR4} ) ₂ , selected from the group consisting of SO2, PO ₍ OR), _NO2 , NO, O, S, _NR5 and nothing;
_R1 , _R2 , _R4 , R5, _{R6 , R7} , _R8 , _R9 , _R10 , _R21 , _R22 , _{R23 , R24, R25} , _R26 and _R27 are independently H, O, _NO2 , substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, selected from the group consisting of substituted and unsubstituted alkylamino, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues;
As used herein, unless otherwise specified, the term "HA" refers to none or a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, bisulfuric acid. , phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucaronic acid, sugar acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or pamoic acid;
Ar is selected from the group consisting of phenyl, 2'-naphthyl, 4-iodophenyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues.

The corresponding parent peptides of peptides HPPs/HPCs with structures 2-343 are listed below in Tables A(I) and (II).
Table A. Parent Peptides of Peptides HPPs/HPCs Having Structures 2-343

Structures of unusual amino acids (Xaa1, Xaa2, Xaa3, Xaa4, Xaa5, Xaa7, Xaa9, Xaa13, Xaa14, Xaa15, Xaa17, Xaa19, Xaa21, Xaa22, Xaa23, Xaa24, Xaa25 and Xaa26) appearing in SEQ ID NOS: 1-172 ) are listed in Table B.
Table B. Unusual Amino Acids Appearing in SEQ ID NOs: 1-172

In certain embodiments, the peptide HPP/HPC comprises a compound selected from the group consisting of structures 2-345 as defined above, including stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein the formula During,
HA, _Ar , _X , _X4 , _X5 , _X6 , _X7 , _X8 , X9, _X10 , X21, _X22 , _X23 , _X24 , _X25 , _X26 and _X27 are as defined above. is defined similarly to;
R is H, substituted and unsubstituted 1-20 carbon alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted 1-20 carbon alkoxy, substituted and selected from the group consisting of unsubstituted 1-20 carbon alkylthio, substituted and unsubstituted 1-20 carbon alkylamino, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues;
_R1 , _R2 , _R4 , R5, _{R6 , R7} , _R8 , _R9 , _R10 , _R21 , _R22 , _R23 , _R24 , _R25 , _R26 and _R27 are independently H, O, substituted and unsubstituted 1-20 carbon alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted 1-20 carbon alkoxy, substituted and unsubstituted 1-20 carbon alkylthio, substituted and unsubstituted 1-20 carbon alkylamino, substituted and unsubstituted 1-20 carbon alkenyl, substituted and unsubstituted 1-20 carbon It is selected from the group consisting of alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues.

構造１ａ

構造１ｂ

構造１ｃ

構造１ｄ

構造１ｅ

構造１ｆ

構造１ｇ

構造１ｈ
その立体異性体及び薬学上許容可能なその塩を含み、式中、
Ｘ₄、Ｘ₅、Ｘ₆、Ｘ₇、Ｘ₈、Ｘ₉、Ｒ₄、Ｒ₅、Ｒ_6、Ｒ₇、Ｒ₈、Ｒ₉及びＨＡは上記と同様に定義される。
ペプチドＨＰＰ／ＨＰＣの固相合成 In certain embodiments, the peptide HPP/HPC comprises a structure selected from the group consisting of Structure 1a, Structure 1b, Structure 1c, Structure 1d, Structure 1e, Structure 1f, Structure 1g, and Structure 1h;

Structure 1a

Structure 1b

structure 1c

structure 1d

Structure 1e

structure 1f

structure 1g

structure 1h
including stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein
_X4 , _X5 , X6, _X7 , _X8 , _X9 , _R4 , _R5 , _{R6 , R7} , _R8 , _R9 and HA are defined as above.
Solid phase synthesis of peptide HPP/HPC

Short peptides (<10 amino acids) can be synthesized by solution phase, but long peptides by solution phase are very difficult to synthesize. The HPPs/HPCs of the disclosed peptides are modified peptides and cannot be synthesized by standard solid-phase peptide synthesis methods (C-terminal to N-terminal).

In certain embodiments, the peptide HPP/HPC is synthesized from N-terminus to C-terminus, wherein the synthetic method comprises the following steps:

Methods for preparing peptide HPC using solid phase synthesis include the following.
a) providing chemically modified resins (e.g. trityl chloride and carbonate resins);
b) the carboxyl groups of all amino acid residues, natural or modified as desired according to peptide HPC, by protecting groups (for example, 2-(4-nitrophenylsulfonyl)ethyl and 9-fluorenylmethyl groups); protecting to provide a COOH-protected amino acid residue;
c) coupling a COOH-protected amino acid residue at the N-terminus of the peptide HPC to a chemically modified resin to provide an immobilized COOH-protected peptide HPC precursor with one amino acid residue; matter;
d) COOH-protected peptide HPC precursor immobilized using a deprotecting reagent (e.g. 1% DBU/20% piperidine/79% DMF or other reagent capable of deprotecting protected carboxyl groups) deprotecting the protected carboxyl group of to provide an immobilized COOH-unprotected peptide HPC precursor with one amino acid residue;
e) step c) with the COOH-protected amino acid residues of the peptide HPC until an immobilized C-unprotected peptide HPC precursor with all amino acids except the C-terminal amino acid residue is provided. and d);
f) linking the C-terminal amino acid residue to _RT via a covalent bond to provide a modified C-terminal amino acid, wherein _RT is substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkyloxy groups, substituted and unsubstituted alkenyl groups, substituted and unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted substituted heteroaryl groups, structure Na, structure Nb, structure Nc, structure Nd, structure Ne, structure Nf, structure Ng, structure Nh, structure Ni, structure Nj, structure Nk, structure Nl, structure is selected from the group consisting of Nm, structure Nn, structure No, structure Np, structure Nq, and structure Nr:
g) coupling a modified C-terminal amino acid to the immobilized C-unprotected peptide HPC precursor obtained from step e) to provide immobilized peptide HPC; and h) immobilized peptide HPC from the resin. to provide peptide HPC.

In certain embodiments, the chemically modified resin can be directly attached to the protected amino acid, or the chemically modified resin is first further modified and then attached to the COOH-protected amino acid. be able to.

In certain embodiments, peptides HPP/HPC containing a transport unit at the C-terminus are prepared by linking the C-terminal amino acid to the peptide chain, wherein the carboxyl group is linked to the transport unit as described above. For example, the transport unit may be structure Na, structure Nb, structure Nc, structure Nd, structure Ne, structure Nf, structure Ng, structure Nh, structure Ni, structure Nj, structure Nk, structure Nl, structure Nm, structure Nn, structure No, structure Np, structure Nq, and structure Nr.

In certain embodiments, a peptide HPP/HPC containing a transport unit at the C-terminus is prepared by attaching the C-terminal amino acid to a peptide chain, during which the carboxyl group is protected, the carboxyl group is deprotected, and the final mechanically connected to the transport unit. For example, the transport unit may be structure Na, structure Nb, structure Nc, structure Nd, structure Ne, structure Nf, structure Ng, structure Nh, structure Ni, structure Nj, structure Nk, structure Nl, structure Nm, structure Nn, structure No, structure Np, structure Nq, and structure Nr.

In certain embodiments, release of peptide HPP/HPC is achieved in high yields. For example, in certain embodiments, the resin is trityl chloride resin and the release step can be accomplished by reacting with TFA/DCM (eg, 5%). In certain embodiments, the resin is a carbonate resin and the release step can be accomplished by reacting with Pd--C (eg 10% in methanol) and H ₂ .

In certain embodiments, the coupling reaction is performed in the presence of a coupling agent. Examples of coupling agents include, without limitation, HBTU/DIPEA/HOBt, TBTU/DIPEA/HOBt, BOP/DIPEA/HOBt, HATU/DIPEA/HOBt and DIC/HOB, and combinations thereof.

As used herein, unless otherwise defined, "DBU" means 1,8-diazabicyclo[5,4,0]undec-7-ene; "DMF" means dimethylformamide;
"DIPWA" means N,N-diisopropylethylamine;
"HBTU" means O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluorophosphate;
"HOBt" means 1-hydroxybenzenetriazole;
"TBTU" means O-benzotriazole-N,N,N',N'-tetramethyl-uronium-tetrafluoroborate;
"BOP" means benzotriazol-1-yl-N-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate;
"HATU" means N-(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethammonium hexafluorophosphate N-oxide;
"DIC" means diisopropylcarbodiimide and "TFA" means trifluoroacetic acid.
II. Pharmaceutical compositions containing HPPs/HPCs

Another aspect of the invention relates to pharmaceutical compositions comprising at least one peptide HPP/HPC and a pharmaceutically acceptable carrier.

The term "pharmaceutically acceptable carrier", as used herein, refers to the transfer from one location, fluid, organ (internal or external), or part of a living organism to another location, fluid, organ, or A pharmaceutically acceptable substance, composition or agent, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating agent, which in part is involved in carrying or transporting the HPP/HPC means vehicle.

Each carrier should be compatible with the other ingredients of the formulation, e.g., HPP/HPC, be compatible with tissues or organs of living systems without undue toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications. "Pharmaceutically acceptable" in the sense of being suitable for use in contact and commensurate with a reasonable benefit/risk ratio.

Some examples of substances that can serve as pharmaceutically acceptable carriers include (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn and potato starch; Cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, (4) powdered tragacanth, (5) malt, (6) gelatin, (7) talc, (8) such as cocoa butter and suppository waxes. (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) such as magnesium hydroxide and aluminum hydroxide; (15) alginate, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) alcohols such as ethyl alcohol and propane alcohol, (20) Phosphate buffer solution, and (21) other non-toxic compatible substances used in pharmaceutical formulations such as acetone.

Pharmaceutical compositions are required for appropriate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like. may contain pharmaceutically acceptable auxiliary substances.

In one embodiment, the pharmaceutically acceptable carrier is an aqueous carrier such as buffered saline. In certain embodiments, pharmaceutically acceptable carriers are polar solvents such as water, acetone and alcohol.

The concentration of HPP/HPC in these formulations can vary widely and is selected primarily based on fluid volume, viscosity, body weight, etc., according to the particular mode of administration chosen and the needs of the biological system. For example, the concentration can be 0.0001 wt% to 100 wt%, 0.001 wt% to 50 wt%, 0.1 wt% to 30v%, 0.1 wt% to 10 wt%.

The compositions of the invention can be administered for prophylactic, therapeutic and/or hygienic use. Such administration is topical, mucosal, e.g., oral, intranasal, vaginal, rectal, parenteral, transdermal, subcutaneous, intramuscular, intravenous, by inhalation, intraocular and other conventional routes. be able to. Pharmaceutical compositions can be administered in a variety of unit dosage forms depending on the method of administration. For example, unit dosage forms suitable for oral administration include powders, tablets, pills and lozenges.

Thus, a typical pharmaceutical composition for intravenous administration is about 10 ⁻¹⁰ g to about 100 g, about 10 ⁻¹⁰ g to about 10 ⁻³ g, about 10 ⁻⁹ g to about 10 ⁻ g per subject per day. ⁶ g, from about 10 ⁻⁶ g to about 100 g, from about 0.001 g to about 100 g, from about 0.01 g to about 10 g, or from about 0.1 g to about 1 g. Dosages from about 0.01 mg to about 50 g per subject per day may be used. The actual methods of preparing parenterally administrable compositions are known or apparent to those skilled in the art and are found in Remington's Pharmaceutical Sciences, 15th Edition, Mack Publishing Company, Easton, Pa.; (1980) for further details.
III. Application of HPPs/HPCs
i) Method of penetrating biological barriers

Another aspect of the invention relates to methods of using the compositions of the invention in penetrating one or more biological barriers in a biological subject. The method includes administering HPP/HPC or a peptide or peptide-related compound, or a pharmaceutical composition thereof, to a living subject. In certain embodiments, HPP/HPC is about 10-fold higher, 50-fold higher, > about 100-fold or higher, > about 200-fold or higher, > about 300-fold higher than its parent drug across one or more biological barriers > about 500 times higher, > about 1000 times higher permeability.

The term “biobarrier” as used herein refers to a biological layer that separates the environment into distinct spatial regions or compartments, the separation regulating (e.g., constraining) passage therethrough. , limit, enhance, nothing happens) and it is possible to penetrate or move substances or objects from one compartment/region to another compartment/region. Different spatial regions or compartments, as referred to herein, may have the same or different chemical or biological environments. Biological layers, as referred to herein, include biological membranes, cell layers, biological structures, interior surfaces of subjects, organisms or body cavities, exterior surfaces of subjects, organisms, organs or body cavities, or any combination or plurality thereof, It is not limited to these.

Examples of biological membranes include lipid bilayer structures, eukaryotic cell membranes, prokaryotic cell membranes, and intracellular membranes (e.g., nuclear or organelle membranes, e.g., Golgi apparatus, rough and smooth endoplasmic reticulum (ER) , ribosomes, vacuoles, vesicles, liposomes, mitochondria, lysosomes, nuclei, chloroplasts, plastids, peroxisomes or membranes or envelopes of microbodies).

A lipid bilayer, as referred to herein, is a double layer of lipidic molecules including, but not limited to, phospholipids and cholesterol. In a particular embodiment, the lipids for the bilayer are amphiphilic molecules consisting of a polar head group and a non-polar fatty acid tail. The bilayer consists of lipids arranged such that their hydrocarbon tails face each other to form an oily core that is supported with a hydrophobic effect, while their charged heads face the aqueous solution on either side of the membrane. Consists of two layers. In another particular embodiment, the lipid bilayer may contain one or more embedded protein and/or sugar molecules.

Examples of cell layers include inner membranes of eukaryotic cells (e.g., epithelium, lamina propria and smooth muscle or muscularis mucosae (of the gastrointestinal tract)), inner membranes of prokaryotic cells (e.g., surface layers, or the same protein or S-layer, which refers to a monolayer of two-dimensional structures composed of glycoproteins, particularly the S-layer, which refers to part of the cell envelope commonly found in bacteria and archaea), biofilms (self-generated polymer matrices) organized communities of micro-organisms encapsulated or attached to living or inert surfaces), and plant cell layers (eg, hulls). The cells may be normal cells or pathological cells (eg, diseased cells, cancer cells).

Examples of biological structures include structures sealed by tight or occlusive junctions that provide a barrier against toxins, bacteria and viruses, such as the blood-milk barrier and the blood-brain barrier (BBB). In particular, the BBB is composed of impermeable endothelium and presents both a physical barrier through tight junctions adjacent to neighboring endothelial cells and a transport barrier composed of efflux transporters. Biological structures may also include mixtures of cells, proteins and sugars (eg, blood clots).

Examples of inner surfaces of subjects, organisms, organs or body cavities include buccal mucosa, esophageal mucosa, gastric mucosa, intestinal mucosa, olfactory bulb mucosa, oral mucosa, bronchial mucosa, uterine mucosa and inner lining (uterine mucosa, pollen grain wall) or spore wall layer), or a combination or plurality thereof.

Examples of external surfaces of subjects, organisms, organs or body cavities include capillaries (e.g. capillaries in cardiac tissue), mucus membranes contiguous with skin (e.g. nostrils, lips, ears, genitalia and anus), organs (e.g. liver , Lungs, Stomach, Brain, Kidneys, Heart, Ears, Eyes, Nose, Mouth, Tongue, Colon, Pancreas, Gallbladder, Duodenum, Rectal, Stomach, Colorectal, Intestines, Blood Vessels, Respiratory System, Blood Vessels, Anorectal and Anus pruritus), the outer surface of the skin, the keratin (e.g., a dead layer of epidermal cells or keratinocytes, or the superimposed superficial layers of cells that cover the hair shaft in animals, the outer multi-layered structure of the epidermis in many invertebrates, plant keratin or polymeric cutin and/or cutan), the outer layer of the wall of the pollen grain or the outer layer of the spore, and combinations or pluralities thereof.

Additionally, biobarriers may further include sugar layers, protein layers, or other biolayers, or a combination or plurality thereof. For example, skin is a biological barrier with multiple biological layers. The skin comprises an epidermal layer (outer surface), an endothelial layer and a subcutaneous layer. The epidermal layers contain the basal cell layer, the spinous cell layer, the granular cell layer and the stratum corneum. Cells in the epidermis are called keratinocytes. The stratum corneum (“squamous layer”) is the outermost layer of the epidermis, the cells of which are flat and squamous (“squamous epithelium”) in shape. These cells contain a lot of keratin and are arranged in superimposed layers that give the skin surface tough, oil- and water-resistant properties.
ii) methods of diagnosing conditions in biological systems

Another aspect of the invention relates to methods of using the compositions of the invention in diagnosing conditions in biological systems. The method includes the steps of:
1) administering a composition comprising the peptide HPP/HPC to a living subject;
2) detecting the presence, location or amount of HPP/HPC, functional units of HPP/HPC or metabolites thereof in a biological subject; and 3) determining a condition in a biological system.

In certain embodiments, HPP/HPC (or agents cleaved from HPP/HPC) aggregate at the site of action where the condition occurs. In certain embodiments, the presence, location or quantity of functional units of HPP/HPC are also detected. In certain embodiments, the onset, progression, progression or remission of a relevant condition (eg cancer) is also determined.

In certain embodiments, the HPP/HPC are labeled with or conjugated to a detection agent. Alternatively, HPP/HPC are prepared to contain a radioisotope for detection. Numerous detection agents are available and are generally grouped into the following categories:
(a) Radioisotopes such as ^35S , ^14C , ^13C , ^15N , ^125I , ^3H and ^131I . Diagnostic agents can be labeled with radioisotopes using techniques known in the art, and radioactivity can be measured using a scintillation counter. Additionally, diagnostic agents can be spin-labeled for electron paramagnetic resonance for carbon and nitrogen labels.
(b) for example, BODIPY, BODIPY analogues, rare earth clays (europium chelates), fluorescein and its derivatives, FITC, 5,6-carboxyl fluorescein, rhodamine and its derivatives, dansyl, lissamine, phycoerythrin, green fluorescent protein, Fluorescent agents such as yellow fluorescent protein, red fluorescent protein, and Texas Red. Fluorescence can be quantified using a fluorometer.
(c) various enzyme-substrate agents such as luciferases (e.g., firefly luciferase and bacterial luciferase), luciferin, 2,3-dihydrophthalazinediones, malate dehydrogenase, urease, peroxidases such as horseradish peroxidase; alkaline phosphatase, β-galactosidase, glucoamylase, lysozyme, saccharide oxidases (eg glucose oxidase, galactose oxidase and glucose-6-phosphate dehydrogenase), heterocyclic oxidases (eg uricase and xanthine oxidase), lactoperoxidase, micro such as peroxidase. Examples of enzyme-substrate combinations include, for example, (i) hydrogen peroxide and horseradish peroxidase as substrates, where the hydrogen peroxidase oxidizes the dye precursor (e.g., orthophenylenediamine (OPD), or 3 ,3′,5,5′-tetramethylbenzidine hydrochloride (TMB); (ii) para-nitrophenyl phosphate and alkaline phosphatase (AP) as chromogenic substrates, and (iii) chromogenic substrates (e.g., p- nitrophenyl-β-D-galactosidase) or -β-D-galactosidase (β-D-Gal) with a fluorescent substrate, 4-methylumbelliferyl-β-D-galactosidase.

In certain embodiments, the detection agent is not necessarily conjugated to a diagnostic agent, but is capable of recognizing the presence of the diagnostic agent and detecting the diagnostic agent.

In certain embodiments, the peptide HPP/HPC may be provided in a kit, ie, a packaged combination of instructions and reagents in predetermined amounts for performing a diagnostic assay. When the HPP/HPC is enzymatically labeled, the kit includes the substrate and any cofactors required by the enzyme (eg, a substrate precursor that provides a detectable chromophore or fluorophore). Additionally, additives such as, for example, stabilizers, buffers (eg, blocking buffers or lysis buffers), etc. may be included. The relative amounts of the various reagents may vary widely to provide a solution concentration of reagents that substantially optimizes the sensitivity of the assay. In particular, the reagents may be provided as dry powders, usually lyophilized, containing excipients that, upon dissolution, provide a reagent solution having the appropriate concentration.
iii) methods of screening substances for desired properties

Another aspect of the invention relates to methods of screening HPP/HPC for desired properties.

In certain embodiments, the method includes:
(1) covalently linking a test functional unit to a transport unit via a linker to form a test composition (or covalently linking a functional unit to a test transport unit via a linker or to the transport unit);
(2) administering the test composition to a biological system;
(3) determining whether the test composition has the desired properties or properties;

In one embodiment, the desired properties include, for example: (1) the ability of the test functional unit to form a highly permeable composition or revert to the parent drug; (2) the permeation capacity and/or permeation rate of the test composition; (3) efficiency and/or effectiveness of the test composition, (4) transport capacity of the test transport unit, and (5) cleavage capacity of the test linker.
iv) methods of treating a condition in a living subject

Another aspect of the invention relates to methods of using the compositions of the invention in treating a condition in a living subject. The method includes administering the pharmaceutical composition to a biological system.

The term "treating" as used herein means to cure, alleviate, inhibit or prevent. The term "treat" as used herein means to cure, alleviate, inhibit or prevent. The term "treatment" as used herein means curing, alleviation, inhibition or prevention.

The terms "biological system", "biological subject" or "subject" as used herein mean an organ, a group of organs, an organism or a group of organisms that work together to perform a particular task. . The term "organism" as used herein means a collection of molecules that act as a more or less stable whole and have the characteristics of life, eg animal, plant, fungal or microbial.

The term "animal" as used herein means eukaryotic organisms characterized by voluntary locomotion. Examples of animals include, but are not limited to, vertebrates (e.g., humans, mammals, birds, reptiles, amphibians, fish, lampreys and lancelets), urochordates (e.g., monkeys, tadpoles, sorbera and sea squirts), stingrays. Gaina (insects, myriapods, maracadopas, arachnids, sea spiders, arthropods, crustaceans, and annelids), arthropods (paraarthropods), and helminths (e.g., rotifers) mentioned.

The term "plant" as used herein means an organism belonging to the kingdom Plantae. Examples of plants include, but are not limited to, seed plants, bryophytes, ferns and the family of fern plants. Examples of seed plants include, without limitation, cycads, ginkgo biloba, conifers, gametophytes, angiosperms. Examples of bryophytes include, but are not limited to, liverworts, pinworts and mosses. Examples of fern plants include, but are not limited to, Ophioglossa (eg, Adder's Tong, Ginseng, and Grape Fern), Rubinaceae, and Grape Fern. Examples of the family of pteridophytes include, but are not limited to, Rhinoceros fern (eg Lycopodium moss, Spike moss and Mizunika), Pinus var.

The term "fungus" as used herein means eukaryotic organisms belonging to the Kingdom Fungi. Examples of fungi include, but are not limited to, Chytridiomycota, Rhinoceros chinensis, Neocalimasticus, Mildew, Glomus, Ascomycota, and Basidiomycota.

The term "microorganism," as used herein, means organisms that are microscopic (eg, on the length scale of micrometers). Examples of microorganisms include, without limitation, bacteria, fungi, archaea, protozoa, and microscopic plants (eg, green algae) and microscopic animals (eg, plankton, planaria and amoeba).

Some examples of conditions that the methods can treat include conditions that can be treated by HPP/HPC parent agents.
v) Methods of using peptide HPP/HPC and pharmaceutical compositions thereof in therapy

Another aspect of the invention uses peptide HPPs/HPCs or pharmaceutical compositions thereof in treating a condition in a biological system or subject by administering the peptide HPPs/HPCs or pharmaceutical compositions thereof to the biological system or subject. Regarding the method.

Peptides and peptide-related compounds can be used to modulate a wide range of biological processes in biological systems. Conditions associated with such biological processes are treatable by the corresponding peptides or peptide-related compounds and are therefore treatable by peptide HPP/HPC and pharmaceutical compositions thereof.

Such conditions include aging, angina pectoris, antithrombin deficiency, arrhythmia, atherosclerosis, atrial fibrillation, atrial flutter, thrombosis, cardiac ischemia, cardiac surgery, cardiomyopathy, cardiovascular abnormalities, carotid artery disease. , chest pain, circulatory disturbance, claudication, collagen vascular disease, congenital heart disease, congestive heart failure, coronary artery disease, diabetes, diabetes and hypertension, dyslipidemia, irregular rhythm, high triglycerides, heart defect, heart disease, heart failure, heart Valvular disease, hemangioma, high cholesterol, hypertriglyceridemia, intermittent claudication, hypertension, Kawasaki disease, heart attack, myocardial ischemia, orthostatic hypotension, peripheral arterial disease, peripheral arterial occlusive disease, peripheral vascular disease , Reynolds disease, smoking cessation, tachycardia (rapid heartbeat), thrombosis, varicose veins, vascular disease, venous pulmonary ulcer, gingivitis, gum disease, bad breath, oral cancer, periodontal disease, temporomandibular disorder, temporal Mandibular joint syndrome, sunburn, acne, aging skin, alopecia, paralysis, athlete's foot, atopic dermatitis, decubitus ulcer, bunion, burn, burn infection, herpes labialis infection , congenital skin disease, contact dermatitis, cutaneous lupus erythematosus, diabetic leg ulcer, eczema, excessive sweating, Fabry's disease, fungal infection, genital herpes, genital warts, hair loss, hair removal, hand dermatitis, head lice , hemangioma, hereditary angioedema, herpes simplex infection, herpes zoster infection, herpetic neuralgia, eruption, ichthyosis, ischemic leg ulcer, keratosis, lupus, male pattern baldness, malignant melanoma, medical prosthesis melanoma, molluscum contagiosum, mycosis fungoides, onychomycosis, pemphigus vulgaris, postherpetic neuralgia, pressure ulcers, psoriasis and psoriatic disorders, psoriatic arthritis, razor burn, rosacea, sarcoidosis , Scalp disorder, trauma tissue, scleroderma, seborrhea, seborrheic dermatitis, herpes zoster, skin cancer, skin infection, skin lipoma, skin wound, solar lentigines, sporotrichosis, staphylococcal skin infection, stasis dermatitis, spreading fissures, systemic fungal infection, sun toxicity, tinea, tinea capitis, tinea versicolor, urticaria, vitiligo, warts, wounds, acromegaly, adrenal cancer, congenital adrenal hyperplasia, diabetes (type I) and type II), diabetes (type I), diabetes (type II), diabetic gastroparesis, diabetic kidney disease, diabetic macular edema, diabetic nephropathy, diabetic retinopathy, diabetic vitreous hemorrhage, dyslipidemia female hormone deficiency/abnormality, Fredrickson type III, hyperlipoproteinemia, growth hormone deficiency/abnormality, gynecomastia, hair removal, hyperlipidemia, hormone deficiency, hot flush, hyperparathyroidism, idiopathic Dwarfism, Indications: Diabetes type II, male hormone deficiency/abnormality, M cCune-Albright syndrome, menopausal disorders, metabolic syndrome, obesity, ovarian cancer, pancreatic cancer, pancreatic disorders, pancreatitis, parathyroid cancer, parathyroid disease, parathyroid disorders, menopause, pubertal disorders, polycystic ovarian syndrome, Postmenopausal disorder, postmenopausal osteopenia, precocious puberty, primary insulin hypersecretion, severe dwarfism, sexual dysfunction, thyroid disease, thyroid disorder, Turner syndrome, Wilms tumor, Wilson disease, abdominal cancer, achalasia, α1 Antitrypsin deficiency, anal fissure, appendicitis, Barrett's esophagus, cholangiocarcinoma, colonic dysfunction, celiac disease, chronic diarrhea, Clostridium difficile-associated diarrhea, colon cancer, colon polyps, colorectal cancer, constipation, Crohn's disease, diabetic gastroparesis , gastrointestinal tumor, duodenal ulcer, Fabry's disease, fecal incontinence, functional dyspepsia, gallbladder disorder, gastric cancer, gastric ulcer, gastroenteritis, gastroesophageal reflux disease, digestive diseases and disorders, gastric paralysis, heartburn, Helicobacter pylori, hemorrhoids , hepatic encephalopathy, ileus, infectious colitis, inflammatory bowel disease, intra-abdominal infection, irritable bowel syndrome, liver disease, liver injury, non-erosive reflux disease, non-ulcer dyspepsia, organ rejection after organ transplantation , postoperative neuralgia and vomiting, vomiting, rectal cancer, rectal disease, recurrent diarrhea, gastric cancer, stomach discomfort, ulcerative colitis, abnormal blood vessels, acute myeloid leukemia, anemia, anemia (non-Hodgkin's lymphoma), non-small cell Lung cancer, anemic cancer, aneurysm, antiphospholipid syndrome, antithrombin deficiency, aplastic anemia, thrombosis, Candida sepsis/candidiasis, chronic renal anemia, Gaucher disease, blood cancer, blood disorder, paroxysmal hemoglobinuria , hemorrhage, hypercalcemia, hypogammaglobulinemia, hyponatremia, idiopathic thrombocytopenic purpura, islet cell carcinoma, leukemia, B-cell lymphoma, lymphoma, multiple myeloma, myelodysplastic syndrome, myocardium Ischemia, obstruction, platelet deficiency, platelet disorder, red blood cell disorder, renal anemia, Sézary syndrome, sickle cell disease, T-cell lymphoma, thalassemia, thrombocytopenia, von Willebrand disease, leukocyte disorder, acquired immunodeficiency syndrome (AIDS), AIDS-related infection, acute rhinitis, allergy, asthma, anal hypoplasia, bacterial infection, stomatitis, celiac disease, cervical dysplasia, chicken pox, chronic fatigue syndrome, common cold, unclassifiable immunodeficiency, bacterial Conjunctivitis, chronic obstructive pulmonary disease, cutaneous candidiasis, cutaneous T-cell lymphoma, cytomegalovirus infection, dermatomyositis, fever, graft-host disease, hepatitis, hepatitis B, hepatitis C, HIV infection, HIV/AIDS, Human papillomavirus infection, low gamma globulin Brinemia, idiopathic inflammatory cardiomyopathy, influenza, intra-abdominal infection, Kaposi's sarcoma, lupus, Lyme tick disease, Mycobacterium aviary complex infection, meningitis, onychomycosis, oral candidiasis, pneumonia, multiple myositis, (inflammatory myopathy), postherpetic neuralgia, primary immunodeficiency disorders, respiratory syncytial virus infection, rheumatic fever, allergic rhinitis, rotavirus infection, sarcoidosis, sepsis and sepsis, sexually transmitted diseases, herpes zoster, Sjögren's syndrome, smallpox, soft tissue infections, staphylococcal infections, staphylococcal skin infections, streptococcal pharyngitis, systemic candidiasis, systemic lupus erythematosus, throat and tonsil infections, urticaria, vancomycin-resistant enterococci, West Nile Viral Infection, Acromegaly, Ankylosing Spondylitis, Bone Loss, Movement Injury, Bone Disease, Bone Metastasis, Chest Pain, Bunion, Bursitis, Carpal Tunnel Syndrome, Cartilage Injury, Chest Pain, Chronic Back Pain, Chronic Leg Pain pain, chronic pain, chronic shoulder pain, claudication, congenital lactic acidosis, connective tissue disease, dermatomyositis, Dupuytren's disease, fibromyalgia, painful shoulder contracture, adhesive capsulitis, gout (hyperuricemia) ), idiopathic inflammatory cardiomyopathy, intermittent claudication, joint injury, knee injury, multiple sclerosis, muscle pain, muscular dystrophy, musculoskeletal disease, myasthenia gravis (chronic weakness), generalized myasthenia gravis disease, orthopedics, osteoarthritis, osteomyelitis, osteoporosis, osteosarcoma, Paget's disease, partial medial knee meniscectomy, parathyroid disease, postmenopausal osteopenia, postmenopausal osteoporosis, reflex coitus Dystrophic neuropathy syndrome, rheumatoid arthritis, sciatica, spinal cord disorder, spinal malignant disease, spinal artificial joint, sprain, tendon injury, tennis elbow, facial spasm, anal dysplasia, benign prostatic hyperplasia, bladder cancer, bladder disorder, Blood cancer, catheter complications, chronic pelvic pain, diabetic kidney disease, enuresis, erectile dysfunction, Fabry's disease, nocturnal polyuria, urogenital prolapse, glomerulonephritis, glomerulosclerosis, idiopathic membranous nephropathy , impotence, interstitial cystitis, kidney cancer, kidney disease, kidney failure, kidney stones, liver cancer, low testosterone, mastectomy, medical prosthetics, nephropathy, Peyronie's disease, premature ejaculation, prostate cancer, prostate disorders, prostate Intraepithelial neoplasia, proteinuria, Reiter's syndrome, renal artery disease, renal cell carcinoma, renal failure, testicular cancer, tyrosinemia, urethral stricture, urinary incontinence, urinary tract infection, urinary tract cancer, male erectile dysfunction and female impotence , systemic blood pressure, abortion, hypertension control, inhibition of platelet aggregation, pulmonary disease, gastrointestinal disease, inflammation, shock, reproduction, fertility, obesity.

Conditions associated with platelet aggregation include, for example, postoperative thromboembolism, carotid endarterectomy, recurrent stenosis after coronary artery neovascularization, thromboembolism complications in chronic atrial fibrillation, aortic coronary artery Obstruction of arterial bypass grafts, heart attack, stroke, multi-infarct dementia, dementia, hemodialysis shunt thrombosis, and complications of arterial embolism in prosthetic heart valves in patients.

Some examples of conditions treatable by methods comprising using peptide HPP/HPC or pharmaceutical compositions thereof include, but are not limited to, peptide hormone-related conditions, inflammation and related conditions, platelet aggregation-related conditions, conditions, neuropeptide-related conditions, microbial-related conditions, and other conditions modulated by peptides or peptide-related compounds.

In certain embodiments, methods of treating a peptide-treatable condition include peptides or peptide-related compounds such as angiotensin, antagonists of angiotensin II, angiotensin II AT2 receptor, antimicrobial peptides, antioxytocin, hormones, antidiuretic hormone , adrenocorticotropic hormone, antimicrobial peptides, anti-inflammatory peptides, bradykinin, antagonists of bradykinin, endothelin peptides, antagonists of endothelin peptides, gastrin, calcitonin, melanocyte-related antigenic peptides, laminin peptides, fibrinogen peptides, EAE induction Peptides, growth hormone, growth hormone-releasing peptide, somatostatin, hormone-releasing hormone, luteinizing hormone-releasing hormone, neuropeptide, melanocyte-stimulating hormone, sleep-inducing peptide, amyloid peptide, tufutosin, retro-invarso-type tufutosin, enterostatin, melanocortin II, and administering opioid peptides and mimetic peptides HPP/HPC to biological systems.

In certain embodiments, a method of treating a peptide hormone-related condition comprises administering a peptide hormone or peptide hormone-related compound HPP/HPC, or a pharmaceutical composition thereof, to a biological system. In biological systems, hormones regulate a wide range of processes such as energy levels, reproduction, growth and development, homeostasis, and responses to environment, stress and injury. Examples of conditions associated with peptide hormones include, but are not limited to:
(a) menopause;
(b) bone diseases: e.g. osteoporosis, Paget's disease and bone metastasis;
(c) deficiency of growth hormone;
(d) hyperthyroidism and hypothyroidism (e) metabolic disorders such as obesity, abnormal blood sugar levels, abnormal blood lipid levels, diabetes (types I and II) and diabetic retinopathy, necrotic ulcers and diabetes-induced complications, including diabetic proteinuria;
(f) abnormal blood pressure, such as hypertension and hypotension;
(g) skin conditions such as psoriasis and psoriatic disorders, acne, cystic acne, purulent or erythematous nodules, comedones, papules, papules, nodules, epidermoid cysts, keratosis, follicles, abnormal Vascular cutaneous lesions, nevi, bruises (nerves), fibroma softness, scleroderma, vitiligo, and related diseases or age spots (melasma);
(h) autoimmune diseases such as discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmune hepatitis, scleroderma, Sjögren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's thyroiditis, juvenile diabetes, Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS) and Crohn's disease;
(i) eye diseases such as glaucoma, intraocular hypertension, decreased visual acuity after ophthalmic surgery, visual acuity in warm-blooded animals damaged by cystoid macular edema, and cataracts;
(j) preeclamptic toxicosis in high-risk women;
(k) male and female impotence;
(j) allergies and asthma; (k) insomnia;
(l) depression and related conditions;
(m) cardiovascular disease, such as heart attack, unstable angina, peripheral occlusive arterial disease and stroke; (n) tumors, such as benign tumors, breast cancer, colorectal cancer, oral cancer, pulmonary or other respiratory cancer of the organ system, skin cancer, uterine cancer, pancreatic cancer, prostate cancer, cancer of the reproductive organs, cancer of the urinary system, leukemia, or other cancers of the blood and lymphoid tissues; and (o) metastasis.

In certain embodiments, a method of treating a microbial-related condition comprises administering an antimicrobial peptide or antimicrobial peptide-related compound HPP/HPC, or a pharmaceutical composition thereof, to a biological system. Examples of microbial-related conditions include, but are not limited to, inflammation and related conditions:
(a) pain;
(b) trauma;
(c) conditions associated with microorganisms;
(d) Inflammation-related conditions such as inflammation of the prostate (prostatitis), prostatic cystitis, prostatic hyperplasia fibrosis, hemorrhoids, Kawasaki syndrome, gastroenteritis, membranous proliferative glomerulonephritis type 1, Bartter's syndrome, chronic uvea inflammation, ankylosing spondylitis, hemophilic arthritis, inflammatory hemorrhoids, post-irradiation (artificial) proctitis, chronic ulcerative colitis, inflammatory bowel disease, cryptitis, periodontal disease , arthritis, and liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum, stomach, colorectal, intestine, vein, respiratory system, blood vessel , an inflammatory condition in an organ selected from the group consisting of anorectal, and anal pruritus.

In certain embodiments, a method of treating a neuropeptide-related condition comprises administering a neuropeptide or neuropeptide-related compound HPP/HPC, or a pharmaceutical composition thereof, to a biological system. Examples of nerve-related conditions include, but are not limited to, pain, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

Other conditions treatable by HPP/HPC, or pharmaceutical compositions thereof, include, but are not limited to, platelet aggregation, e.g., post-surgical thromboembolism, carotid endarterectomy, post-neovascular stenosis of coronary arteries. complication of thromboembolism in chronic atrial fibrillation, occlusion of aortocoronary-arterial bypass grafts, heart attack, stroke, multi-infarct dementia, dementia, hemodialysis shunt thrombosis, and arterial embolism in prosthetic heart valves in patients Complication-related conditions; pre- and postpartum, anti-AD activity, antidiuretic activity, brain trauma, calcium homeostasis, melanocytes, CNS activity and phagocytosis.

In certain embodiments, a method of treating a condition in a subject ameliorateable or treatable with a peptide or peptide-related compound comprises administering to the subject a therapeutically effective amount of a peptide HPP/HPC or pharmaceutical composition thereof. include.

HPP/HPC or pharmaceutical compositions thereof may be administered orally, enterally, buccal, intranasally, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, intraocular, pulmonary, subcutaneous, and/or parenteral. can be administered to a biological system by any route of administration known in the art, including but not limited to administration of Pharmaceutical compositions can be administered in a variety of unit dosage forms depending on the method of administration.

Parenteral administration includes intravenous, intramuscular, intraarterial, intramedullary, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, intradermal, intraarticular, subcapsular, arachnoidal It generally refers to routes of administration involving injection, including, but not limited to, infra, intraspinal and/or intrasternal injection and/or infusion.

HPP/HPC or pharmaceutical compositions thereof can be provided to the subject in the form of formulations or preparations suitable for each route of administration. Formulations useful in the methods of the invention comprise one or more HPP/HPC, one or more pharmaceutically acceptable carriers therefor, and optionally other therapeutic ingredients. The formulations may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. The amount of HPP/HPC that can be combined with a carrier material to produce a pharmaceutically effective dose is generally that amount of HPP/HPC that produces a therapeutic effect. Generally, from 100 percent, this amount ranges from about 1 percent to about 99 percent HPP/HPC, preferably from about 20 percent to about 70 percent.

Methods of preparing these formulations or compositions include combining HPP/HPC with one or more pharmaceutically acceptable carriers and one or more accessory ingredients. In general, the formulations are prepared by intimately bringing into association the HPP/HPC with liquid carriers or finely divided solid carriers and then, if necessary, shaping the product.

Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (with flavored bases, usually sucrose and acacia or tragacanth), powders, granules, aqueous liquids. or as a solution or suspension in a non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as a lozenge (with inert bases such as gelatin and glycerin, or sucrose and acacia ), and/or mouthwash, etc., each containing a predetermined amount of HPP/HPC as an active ingredient. A compound may also be administered as a bolus, electuary or paste.

In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules, etc.), HPP/HPC is combined with one or more pharmaceutically acceptable carriers such as sodium citrate or calcium phosphate, and/or or the following: (1) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or (3) humectants such as glycerol; (4) disintegrants such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate. (5) solution retardants such as paraffin; (6) absorption enhancers such as quaternary ammonium compounds; (7) humectants such as acetyl alcohol and glycerol monostearate; (8) kaolin and (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; (10) mixed with any of the coloring agents. . In the case of capsules, tablets and pills, the pharmaceutical composition may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using excipients such as lactose and milk sugar, as well as high molecular weight polyethylene glycols.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may contain binders (eg gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (eg sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents. Or it may be prepared using a dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered peptide or peptidomimetic moistened with an inert liquid diluent. Tablets and other dosage forms such as dragees, capsules, pills, and granules may optionally be divided or prepared with coatings or shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. . For example, various ratios of hydroxypropyl methylcellulose can be used to provide desired release characteristics, other polymeric matrices, liposomes and/or microspheres to provide delayed or controlled release of HPP/HPC therein. They may be formulated. They may also be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or other sterile injectable medium immediately prior to use. can do. These compositions may also optionally contain a depressant to release the HPP(s)/HPC(s) only, or preferentially, at specific sites of the gastrointestinal tract, optionally in a delayed manner. It may be a composition that Implantable compositions that can be used include polymeric substances and waxes. The HPP/HPC can also be in microencapsulated form, optionally with one or more of the above excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to HPP/HPC, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate. , ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed, peanut, corn, germ, castor and sesame), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preserving agents.

Suspensions, in addition to HPP/HPC, include, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. It may contain suspending agents such as

Formulations for rectal or vaginal administration may be presented as a suppository, which comprises one or more HPPs/HPPs with one or more suitable excipients or carriers including, for example, cocoa butter, polyethylene glycols, suppository waxes or salicylates. It may be prepared by mixing HPC, which is solid at room temperature but liquid at body temperature, so that it dissolves in the rectal or vaginal cavity and releases the active agent. Formulations suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations, optionally containing carriers as known in the art.

Formulations for topical or transdermal or epidermal or cutaneous administration of HPP compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier such as water, ethanol and ethanol solutions, and with any preservatives, buffers or propellants that may be required. Ointments, pastes, creams and gels contain, in addition to HPP compositions, e.g. It may contain excipients such as admixtures. Powders and sprays can contain, in addition to the HPP composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

HPP/HPC or pharmaceutical compositions thereof can alternatively be administered by aerosol. This can be accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the HPPs/HPCs. A non-aqueous (eg, fluorocarbon propellant) suspension may be used. Sonic nebulizers can also be used. Aqueous aerosols are made by formulating an aqueous solution or suspension of the agent with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers will vary according to the requirements of the particular compound, but usually include nonionic surfactants (Tween, Pluronics or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, glycine. amino acids, buffers, salts, sugars or sugar alcohols such as
Aerosols generally are prepared from isotonic solutions.

HPP compositions can also be delivered to tumor sites using transdermal patches. Such formulations may be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can be used to increase the flux of the peptidomimetic across the skin. The rate of such flow can be controlled by providing a rate-limiting membrane or dispersing the peptidomimetic in a polymer matrix or gel.

In certain embodiments, the transdermal therapeutic application system comprises peptide HPP/HPC as an active agent for treating a condition treatable by its parent compound, wherein the system is capable of dissolving the peptide HPP/HPC. It is a solution that is used by spraying or applying, further containing a solvent. Examples of solvents include, without limitation, organic and inorganic solvents such as water, ethanol, isopropanol, acetone, DMSO, DMF, and combinations thereof.

In certain embodiments, the transdermal therapeutic application system comprises the peptide HPP/HPC as an active agent for treating a condition treatable by its parent compound, the system further comprising a matrix layer containing the active agent and a non-active agent-containing matrix layer. It includes a main portion including a permeable backing layer. In certain embodiments, such bodies are patches or bandages. In certain embodiments, such body is a reservoir of active agent comprising a permeable bottom facing the skin, wherein by controlling the rate of release the system regulates the active ingredient or active ingredients. It allows metabolites to consistently reach optimal therapeutic blood levels, increasing efficacy and reducing side effects of the active ingredient or metabolites of the active ingredient.

Ophthalmic formulations, eye ointments, powders, solutions and the like are also contemplated as being within the scope of this invention.

Formulations suitable for parenteral administration include one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or reconstitution into sterile injectable solutions or dispersions immediately prior to use. HPP/HPC in combination with a sterile powder that may be formulated, which may include antioxidants, buffers, bacteriostats, solutes to render the formulation isotonic with the blood of the intended recipient, or suspending agents. Or you may contain a thickener.

Examples of suitable aqueous and non-aqueous carriers that may be employed in formulations suitable for parenteral administration include water, ethanol, polyols (eg, glycerol, propylene glycol, polyethylene glycol, etc.), and suitable carriers thereof. vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

Formulations suitable for parenteral administration may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of microbial action may be ensured by inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenolsorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. Additionally, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as, for example, aluminum monostearate and gelatin.

Injectable depot forms are made by forming microencapsule matrices of HPP/HPC or in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled by the ratio of HPP/HPC and polymer, and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the HPP/HPC in liposomes or microemulsions that are compatible with body tissues.

In certain embodiments, the peptide HPP/HPC or pharmaceutical composition thereof is delivered to the site of disease or tumor at a therapeutically effective dose. As is known in the pharmaceutical arts, the exact amount of pharmaceutically effective dose of HPP/HPC that produces the most effective results in terms of therapeutic efficacy in a given patient is, for example, a few Specific HPP/HPC activity, specific properties, pharmacokinetics, pharmacokinetics, and bioavailability, physiological conditions of the subject (race, age, sex, weight, diet, type and stage of disease, to name but a few). , general condition, response to a given dose and type of drug), the nature of the pharmaceutically acceptable carrier in the formulation, the route and frequency of administration used, and the severity and severity of disease caused by the pathogenic target microorganism. subject to trends. However, the guidelines above can be used as a basis for fine-tuning therapy, e.g., determining optimal dosages for administration, requiring only routine experimentation consisting of monitoring the subject and adjusting dosages. and not. Remington: The Science and Practice of Pharmacy (Edited by Gennaro, 20. sup. th edition, Williams & Wilkins PA, USA) (2000).
IV. advantage

Peptides and related compounds are hydrophilic and have a limited ability to penetrate the skin membrane barrier. When taken orally, peptides and related compounds can be rapidly proteolyzed by proteolytic enzymes in the gastrointestinal tract within minutes. In the case of injections, administration of peptides is painful and often requires frequent and costly hospital visits to treat chronic conditions.

In certain embodiments, the peptide HPP/HPC is capable of crossing one or more biological barriers with greater efficiency than the parent compound, and HPP/HPC is administered locally (topically or transdermally). can reach a position where the condition occurs without the need for systemic administration (eg, oral or parenteral administration). Local administration and permeation of HPP/HPC achieves the same level of local concentration of agent or agent at a lower amount or dose of HPP/HPC than systemic administration of the parent agent or parent drug. or, if possible, reach higher levels of local concentration that may not be obtainable with systemic administration or require significantly higher dosages of the agent with systemic administration. . HPP/HPC or, if cleaved, high local concentrations of the parent agent allow for more effective and rapid treatment of the condition than systemically delivered parent agents, which may not previously have been possible; Or allow treatment of new conditions that may go unobserved. Local administration of HPP/HPC allows biological subjects to reduce potential suffering from systemic administration, e.g., adverse reactions associated with systemic exposure to agents, gastrointestinal/renal effects do. Furthermore, local administration avoids the need for systemic administration (e.g., injection) as HPP/HPC traverses multiple biological barriers and reaches the whole body, e.g. Allows to forestall associated pain.

In certain embodiments, the HPP/HPC or pharmaceutical compositions thereof of the present invention can be administered systemically (eg, transdermally, orally or parenterally). HPP/HPC or HPP/HPC active agents (eg, drugs or metabolites) enter the systemic circulation at a faster rate than the parent agent, which may provide more rapid access to the site of action for the condition. In addition, HPP/HPC can cross biological barriers (e.g., the blood-brain barrier) that were impenetrable when the parent drug was administered alone, a condition that may not have previously been possible or appreciated. can provide a novel treatment for

For example, the peptide HPP/HPC has a higher penetration rate across biological barriers (eg, > about 10-fold, > about 50-fold, > about 100-fold, > about 200-fold than the peptide or peptide-related compound administered alone). times, >about 300-fold, >about 1000-fold higher). Side effects (e.g., vomiting, hair loss, susceptibility to infection) were observed in subjects receiving the parent peptide at similar doses, while no or few adverse side effects were observed in subjects receiving the peptide HPP/HPC. can't
V. Example

The following examples are provided to better illustrate the claimed invention, but they should in no way be construed as limiting the scope of the invention. All of the specific compositions, materials and methods described below fall within the scope of the invention, in whole or in part. These specific compositions, materials and methods are not intended to be limiting of the present invention, but merely illustrate specific embodiments falling within the scope of the present invention. One skilled in the art may develop equivalent compositions, materials and methods without departing from the scope of the present invention without exercising inventive capacity. It will be appreciated that many variations can be made in the procedures described herein and still fall within the confines of the invention. It is the intent of the inventors that such mutations are included within the scope of the present invention.
Example 1. Preparation of HPP/HPC from Parent Drugs Preparation of HPP/HPC from Parent Drugs Containing At Least One Carboxyl Group

構造Ｆ－Ｃ
を有する親化合物を構造Ｌ－１

構造Ｌ－１
を有するＨＰＰ／ＨＰＣに変換し、それはその立体異性体及び薬学上許容可能な塩を含み、式中、
Ｆ、Ｌ_1C、Ｌ_1N、Ｌ_2C、Ｌ_2N、Ｌ_4C及びＬ_4Nは上記のように定義され；
Ｔ_Cは、ペプチドＨＰＰ／ＨＰＣの輸送ユニットである。たとえば、Ｔ_Cは、上記で定義されたような構造Ｎａ，構造Ｎｂ，構造Ｎｃ，構造Ｎｄ，構造Ｎｅ，構造Ｎｆ，構造Ｎｇ，構造Ｎｈ，構造Ｎｉ，構造Ｎｊ，構造Ｎｋ，構造Ｎｌ，構造Ｎｍ，構造Ｎｎ，構造Ｎｏ，構造Ｎｐ，構造Ｎｑ，及び構造Ｎｒから成る群から選択され：
Ｔ_Nは、無、Ｈ，置換及び非置換のアルキル基、置換及び非置換のシクロアルキル基、置換及び非置換のヘテロシクロアルキル基、置換及び非置換のアルキルオキシ基、置換及び非置換のアルケニル基、置換及び非置換のアルキニル基、置換及び非置換のアリール基、置換及び非置換のヘテロアリール基から成る群から選択される。 In certain embodiments, the following structures FC

Structure FC
A parent compound having structure L-1

Structure L-1
which includes stereoisomers and pharmaceutically acceptable salts thereof, wherein
F, L _1C , L _1N , L _2C , L _2N , L _4C and L _4N are defined as above;
T _C is the transport unit of the peptide HPP/HPC. For example, T _C can be structure Na, structure Nb, structure Nc, structure Nd, structure Ne, structure Nf, structure Ng, structure Nh, structure Ni, structure Nj, structure Nk, structure Nl, structure is selected from the group consisting of Nm, structure Nn, structure No, structure Np, structure Nq, and structure Nr:
T _N is none, H, substituted and unsubstituted alkyl group, substituted and unsubstituted cycloalkyl group, substituted and unsubstituted heterocycloalkyl group, substituted and unsubstituted alkyloxy group, substituted and unsubstituted alkenyl substituted and unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heteroaryl groups.

構造Ｄ
（たとえば、酸ハライド、親化合物の混合無水物など）を有する親化合物又は親化合物の誘導体を構造Ｅ：Ｔ_C－Ｌ_2C－Ｈの化合物と反応させること（スキーム１）による有機合成に従って調製され、式中、
Ｗ_Cは、ＯＨ、ハロゲン、アルコキシカルボニル及び置換アリールオキシカルボニルから成る群から選択され；
Ｆ、Ｌ_1C、Ｌ_1N、Ｌ_2C、Ｌ_2N、Ｌ_4C、Ｌ_4N、Ｔ_C及びＴ_Nは上記のように定義される。

スキーム１．親化合物からのＨＰＰ／ＨＰＣの調製（Ｉ） In certain embodiments of the invention, the HPP/HPC having structure L-1 has structure D

Structure D
(e.g., acid halides, mixed anhydrides of the parent compound, etc.) by reacting the parent compound or a derivative of the parent compound with a compound of structure E: T _C -L _2C -H (Scheme 1). , where
W _C is selected from the group consisting of OH, halogen, alkoxycarbonyl and substituted aryloxycarbonyl;
F, L _1C , L _1N , L _2C , L _2N , L _4C , L _4N , T _C and T _N are defined as above.

Scheme 1. Preparation of HPP/HPC from Parent Compounds (I)

In certain embodiments, HPP/HPC having structure L-1 are prepared according to Scheme 1 as described above, wherein L _4C is C═O.

構造Ｆ－Ｎ
を有する親化合物が、以下の構造Ｗ：

構造Ｗ
を有する化合物と反応して構造Ｌ

構造Ｌ－１
のＨＰＰ／ＨＰＣが得られ、その立体異性体及び薬学上許容可能な塩を含み、式中、
Ｆ、Ｌ_1C、Ｌ_1N、Ｌ_2C、Ｌ_2N、Ｌ_4C、及びＬ_4Nは上記のように定義され
Ｔ_Nは、ペプチドＨＰＰ／ＨＰＣの輸送ユニットである。たとえば、Ｔ_Nは、上記で定義されたような構造Ｎａ，構造Ｎｂ，構造Ｎｃ，構造Ｎｄ，構造Ｎｅ，構造Ｎｆ，構造Ｎｇ，構造Ｎｈ，構造Ｎｉ，構造Ｎｊ，構造Ｎｋ，構造Ｎｌ，構造Ｎｍ，構造Ｎｎ，構造Ｎｏ，構造Ｎｐ，構造Ｎｑ，及び構造Ｎｒから成る群から選択され：
Ｔ_Cは、無、Ｈ，置換及び非置換のアルキル基、置換及び非置換のシクロアルキル基、置換及び非置換のヘテロシクロアルキル基、置換及び非置換のアルキルオキシ基、置換及び非置換のアルケニル基、置換及び非置換のアルキニル基、置換及び非置換のアリール基、置換及び非置換のヘテロアリール基から成る群から選択され；
Ｗ_Nは、ＯＨ、ハロゲン、アルコキシカルボニル及び置換アリールオキシカルボニルオキシから成る群から選択される（スキーム２）。

スキーム２．親化合物からのＨＰＰ／ＨＰＣの調製（ＩＩ） In certain embodiments, Structure F:

Structure FN
A parent compound having the following structure W:

Structure W
structure L by reacting with a compound having

Structure L-1
of HPP/HPC, including stereoisomers and pharmaceutically acceptable salts thereof, wherein
F, L _1C , L _1N , L _2C , L _2N , L _4C and L _4N are defined as above _TN is the transport unit of the peptide HPP/HPC. For example, T _N is structure Na, structure Nb, structure Nc, structure Nd, structure Ne, structure Nf, structure Ng, structure Nh, structure Ni, structure Nj, structure Nk, structure Nl, structure is selected from the group consisting of Nm, structure Nn, structure No, structure Np, structure Nq, and structure Nr:
T _C is none, H, substituted and unsubstituted alkyl group, substituted and unsubstituted cycloalkyl group, substituted and unsubstituted heterocycloalkyl group, substituted and unsubstituted alkyloxy group, substituted and unsubstituted alkenyl substituted and unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heteroaryl groups;
W _N is selected from the group consisting of OH, halogen, alkoxycarbonyl and substituted aryloxycarbonyloxy (Scheme 2).

Scheme 2. Preparation of HPP/HPC from parent compound (II)

In certain embodiments, HPP/HPC having the structure of structure L-2 is conjugated with, for example, —COOH, —NH ₂ , — Prepared by organic synthesis that protects undesirable reactive sites such as OH or SH. In certain embodiments, the resulting protected HPP/HPC may be further partially or fully deprotected to partially protected HPP/HPC or deprotected HPP/HPC, respectively. .
Preparation of Ac-Val-Pro-Asp(OEt)-Pro-Arg( _diAc ) _{-OCH2CH2N ( CH2CH3} ) _2.HCl

Preparation of H-Arg(diAc)-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ : 30.8 g A-Arg-OH was dissolved in 500 mL acetone. 200 mL of 20% NaOH was added to the reaction mixture. 40 g of acetic anhydride was added dropwise to the reaction mixture. The mixture was stirred for 2 hours at room temperature (RT). The solvent was evaporated. The residue was extracted with 500 mL of ethyl acetate. The ethyl acetate solution was washed with water (3 x 100 mL). The ethyl acetate layer was dried over magnesium sulfate. The ethyl acetate solution was evaporated to dryness. The residue (Z-Arg(diAc)-OH, 30 g) was dissolved in 300 mL of acetonitrile. The mixture was cooled to 0° C. in an ice-water bath. 12 g of N,N-diethylaminoethanol, 2 g of 4-dimethylaminopyridine and 22 g of 1,3-dicyclohexylcarbodiimide were added to the reaction mixture. The reaction mixture was stirred at 0° C. for 1 hour and at RT overnight. Solids were removed by filtration and the solution was evaporated to dryness. The residue was extracted with ethyl acetate (2×250 mL). The ethyl acetate solution was washed with 5% sodium bicarbonate (1 x 500 mL) and water (3 x 100 mL). The ethyl acetate solution was dried over magnesium sulfate. The solution was evaporated to dryness. The residue [Z-Arg(diAc)-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ , 28 g] was dissolved in 300 mL of methanol. 2 g of 10% Pd/C was added to the solution. The mixture was stirred at RT under hydrogen for 10 hours. Pd/C was removed by filtration. The solution was evaporated to dryness to give 22 g of H--Arg(diAc)--OCH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ .

Preparation of Boc-Asp(OEt)-Pro-OSu: 15 g of L-proline was dissolved in 300 mL of 10% sodium bicarbonate. 150 mL of acetone and 36 g of Boc-Asp(OEt)-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 hours. The mixture was washed with ether (1 x 300 mL). 500 mL of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice-cold 3N HCl. The ethyl acetate layer was collected and washed with water (3x300 mL). Organic solutions were dried over sodium sulfate. The solution was evaporated to dryness. 25 g of residue (Boc-Asp(OEt)-Pro-OH) and 11 g of N-hydroxysuccinimide were dissolved in 300 mL of dichloromethane. The mixture was cooled to 0°C. 16 g of 1,3-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0° C. for 1 hour. Solids were removed by filtration. The dichloromethylene solution was washed with 5% sodium bicarbonate (1 x 200 mL) and water (3 x 200 mL). Organic solutions were dried over sodium sulfate. The solution was evaporated to dryness to give 28 g of Boc-Asp(OEt)-Pro-OSu.

H-Asp(OEt)-Pro-Arg(diAc)-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ . Preparation of 2TFA: 22 g of H-Arg(diAc)-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ were dissolved in 300 mL of 5% NaHCO ₃ . 24 g of Boc-Asp(OEt)-Pro-OSu in 150 mL of acetone was added to the reaction mixture. The mixture was stirred at RT for 5 hours. 500 mL of ethyl acetate was added to the mixture. The ethyl acetate solution was washed with water (3 x 100 mL). Organic solutions were dried over sodium sulfate. The solution was evaporated to dryness. The residue was dissolved in 250 mL of dichloromethane. 200 mL of trifluoroacetic acid was added to the mixture and the mixture was stirred for 30 minutes. The mixture was evaporated to dryness to give 32 g of H-Asp(OEt)-Pro-Arg(diAc)-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ . 2TFA was obtained.

Preparation of Ac-Val-Pro-OSu: 15 g of L-proline was dissolved in 300 mL of 10% sodium bicarbonate. 150 mL of acetone and 26 g of Ac-Val-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 hours. The mixture was washed with ether (1 x 300 mL). 500 mL of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice-cold 3N HCl. The ethyl acetate layer was collected and washed with water (3 x 300 mL). Organic solutions were dried over sodium sulfate. The solution was evaporated to dryness. 20 g of residue (Ac-Val-Pro-OH) and 11 g of N-hydroxysuccinimide were dissolved in 300 mL of dichloromethane. The mixture was cooled to 0°C. 16 g of 1,3-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0° C. for 1 hour. Solids were removed by filtration. The dichloromethylene solution was washed with 5% sodium bicarbonate (1 x 200 mL) and water (3 x 200 mL). Organic solutions were dried over sodium sulfate. The solution was evaporated to dryness to give 20 g of Ac-Val-Pro-OSu.

Preparation of Ac-Val-Pro-Asp(OEt)-Pro-Arg(diAc)-OCH ₂ CH ₂ N(CH ₂ CH ₃ )2.HCl: 31 g of H-Asp(OEt)-Pro-Arg(diAc) -OCH ₂ CH ₂ N(CH ₂ CH ₃ ) _2.2TFA was dissolved in 300 mL of 10% sodium bicarbonate. 150 mL of acetone and 15 g of Ac-Val-Pro-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 hours. 500 mL of ethyl acetate was added to the mixture. The organic layer was washed with water (3 x 100 mL). The ethyl acetate layer was dried over sodium sulfate. Sodium sulfate was removed by filtration. 15 g of HCl gas in dioxane (200 mL) was added to the solution. The solid was collected and washed with ether (3 x 50 mL). After drying, 20 g of the desired product (hygroscopic product) were obtained. Elemental analysis: _{C39H66ClN9O11 ; molecular} weight: _872.45 . Calculated % C: 53.69; H: 7.62; Cl: 4.06; N: 14.45; O: 20.17; Observed % C: 53.61; 4.10; N: 14.40, O: 20.22. MS: m/e: 836.4; m/e+1: 836.4.
Preparation of Ac-Tyr(Ac)-Gly-Gly-Phe-Met _{- OCH2CH2N ( CH2CH3} ) _2.HCl

Preparation of H-Met-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ .TFA: 25 g of Boc-Met-OH was dissolved in 300 mL of dichloromethane. The mixture was cooled to 0° C. in an ice-water bath. 12 g of N,N-diethylaminoethanol, 2 g of 4-dimethylaminopyridine and 22 g of 1,3-dicyclohexylcarbodiimide were added to the reaction mixture. The reaction mixture was stirred at 0° C. for 1 hour and at RT overnight. Solids were removed by filtration and the dichloromethane solution was washed with 5% sodium bicarbonate (1 x 500 mL) and water (3 x 100 mL). The ethyl acetate solution was dried over sodium sulfate. The solution was evaporated to dryness. The residue [Boc-Met-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) _{2 ,} 30 g] was dissolved in 250 mL of dichloromethane. 250 mL of trifluoroacetic acid was added to the mixture and the mixture was stirred for 30 minutes. The solution was evaporated to dryness to give 26 g of H-Met-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ .TFA.

Preparation of Boc-Gly-Phe-OSu: 20 g of L-phenylalanine was dissolved in 300 mL of 10% sodium bicarbonate. 150 mL of acetone and 28 g of Boc-Gly-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 hours. The mixture was washed with ether (1 x 300 mL). 500 mL of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice-cold 3N HCl. The ethyl acetate layer was collected and washed with water (3 x 300 mL). Organic solutions were dried over sodium sulfate. The solution was evaporated to dryness. 22 g of residue (Boc-Gly-Phe-OH) and 10 g of N-hydroxysuccinimide were dissolved in 300 mL of dichloromethane. The mixture was cooled to 0°C. 15 g of 1,3-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0° C. for 1 hour. Solids were removed by filtration. The dichloromethylene solution was washed with 5% sodium bicarbonate (1 x 200 mL) and water (3 x 200 mL). Organic solutions were dried over sodium sulfate. The solution was evaporated to dryness to give 25 g of Boc-Gly-Phe-OSu.

Preparation of Gly-Phe-Met-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ .TFA: 25 g of H-Met-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ .TFA in 300 mL of 5% NaHCO ₃ dissolved in 22 g of Boc-Gly-Phe-OSu in 150 mL of acetone was added to the reaction mixture. The mixture was stirred at RT for 5 hours. 500 mL of ethyl acetate was added to the mixture. The ethyl acetate solution was washed with water (3 x 100 mL). Organic solutions were dried over sodium sulfate. The solution was evaporated to dryness. The residue was dissolved in 250 mL of dichloromethane. 200 mL of trifluoroacetic acid was added to the mixture and the mixture was stirred for 30 minutes. The mixture was evaporated to dryness to give 25 g of Gly-Phe-Met-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) ₂ .TFA.

Preparation of Ac-Tyr(Ac)-Gly-OSu: L-glycine was dissolved in 300 mL of 10% sodium bicarbonate. 150 mL of acetone and 36 g of Ac-Tyr(Ac)-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 hours. The mixture was washed with ether (1 x 300 mL). 500 mL of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice-cold 3N HCl. The ethyl acetate layer was collected and washed with water (3 x 300 mL). Organic solutions were dried over sodium sulfate. The solution was evaporated to dryness. 28 g of residue (Ac-Tyr(Ac)-Gly-OH) and 13 g of N-hydroxysuccinimide were dissolved in 300 mL of dichloromethane. The mixture was cooled to 0°C. 18 g of 1,3-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0° C. for 1 hour. Solids were removed by filtration. The dichloromethylene solution was washed with 5% sodium bicarbonate (1 x 200 mL) and water (3 x 200 mL). Organic solutions were dried over sodium sulfate. The solution was evaporated to dryness to give 20 g of Ac-Tyr(Ac)-Gly-OSu.

Preparation of Ac-Tyr(Ac)-Gly-Gly-Phe-Met _- OCH2CH2N( _CH2CH3 ) _2.HCl : 24 g of H-Gly-Phe _- Met _{- OCH2CH2N ( CH2 CH3} ) ₂ -TFA was dissolved in 300 mL of 10% sodium bicarbonate. 150 mL of acetone and 15 g of Ac-Tyr(Ac)-Gly-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 hours. 500 mL of ethyl acetate was added to the mixture. The organic layer was washed with water (3 x 100 mL). The ethyl acetate layer was dried over sodium sulfate. Sodium sulfate was removed by filtration. 15 g of HCl gas in dioxane (200 mL) was added to the solution. The solid was collected and washed with ether (3 x 50 mL). After drying, 18 g of the desired product (hygroscopic product) was obtained. Elemental analysis: _{C37H53ClN6O9S ; molecular} weight: _793.37 . Calculated % C: 56.01; H: 6.73; Cl: 4.47; N: 10.59; O: 18.15; Observed % C: 55.96; H: 6.76; Cl: 4.52; N: 10.54, O: 18.19; MS: m/e: 757.4; m/e+1: 758.4.
Preparation of Ac-Val-Pro-Gly-Pro-Arg( _diAc ) _{-OCH2CH2N ( CH2CH3} ) _2.HCl

Preparation of Boc-Gly-Pro-OSu: 15 g of L-proline was added to 300 mL of 10% sodium bicarbonate. 150 mL of acetone and 27.2 g of Boc-Gly-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 hours. The mixture was washed with ether (1 x 300 mL). 500 mL of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice-cold 3N HCl. The ethyl acetate layer was collected and washed with water (3 x 300 mL). Organic solutions were dried over sodium sulfate. The solution was evaporated to dryness. 21 g of residue (Boc-Gly-Pro-OH) and 11 g of N-hydroxysuccinimide were dissolved in 300 mL of dichloromethane. The mixture was cooled to 0°C. 17 g of 1,3-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0° C. for 1 hour. Solids were removed by filtration. The dichloromethylene solution was washed with 5% sodium bicarbonate (1 x 200 mL) and water (3 x 200 mL). Organic solutions were dried over sodium sulfate. The solution was evaporated to dryness to give 23 g of Boc-Gly-Pro-OSu.

Preparation of H-Gly-Pro-Arg(diAc) _-OCH2CH2N ( _CH2CH3 ) _2.2TFA : 22 g of H _- Arg _{( diAc} ) _{-OCH2CH2N ( CH2CH3} ) ₂ Dissolved in 300 mL of 5% NaHCO ₃ . 20 g of Boc-Gly-Pro-OSu in 150 mL of acetone was added to the reaction mixture. The mixture was stirred at RT for 5 hours. 500 mL of ethyl acetate was added to the mixture. The ethyl acetate solution was washed with water (3 x 100 mL). Organic solutions were dried over sodium sulfate. The solution was evaporated to dryness. The residue was dissolved in 250 mL of dichloromethane. 200 mL of trifluoroacetic acid was added to the mixture and the mixture was stirred for 30 minutes. The mixture was evaporated to dryness to give 28 g of H-Gly-Pro-Arg(diAc)-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) _2.2TF .

Preparation of Ac-Val-Pro-Gly-Pro-Arg( _diAc ) _{-OCH2CH2N ( CH2CH3} ) _2.HCl : 26 g of H-Gly-Pro-Arg( _diAc ) _-OCH2CH2N ( _CH2CH3 ) _2.2TFA was dissolved in ₃₀₀ mL of 10% sodium bicarbonate. 150 mL of acetone and 15 g of Ac-Val-Pro-OSu were added to the reaction mixture. The mixture was stirred at RT for 5 hours. 500 mL of ethyl acetate was added to the mixture. The organic layer was washed with water (3 x 100 mL). The ethyl acetate layer was dried over sodium sulfate. Sodium sulfate was removed by filtration. 15 g of HCl gas in dioxane (200 mL) was added to the solution. The solid was collected, washed with ether (3×50 mL) and dried to give 18 g of desired product (hygroscopic product). Elemental analysis: _{C35H60ClN9O9 ; molecular} weight: _786.36 . Calculated % C: 53.46; H: 7.69; Cl: 4.51; N: 16.03; O: 18.31; Observed % C: 53.43; 4.55; N: 16.01, O: 18.29. MS: m/e: 750.4; m/e+1: 751.4.
Preparation of Cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) _2.HCl

Preparation of Ac-Nle-Asp(OFm)-OH: 43 g of H-Asp(OFm)-OH.TFA and 27 g of Ac-Nle-OSu were dissolved in 300 mL of acetone. 300 mL of 5% NaHCO ₃ was added to the reaction mixture. The mixture was stirred at RT for 5 hours. The mixture was washed with ether (1 x 300 mL). 500 mL of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice-cold 3N HCl. The ethyl acetate layer was collected and washed with water (3 x 300 mL). Organic solutions were dried over sodium sulfate. The solution was evaporated to dryness to give 42 g of Ac-Nle-Asp(OFm)-OH.

Preparation of Fmoc-Trp-Lys(4-Pyoc)-OH: References (H. Kunz and S. Birnbach, Tetrahedron Lett., 25, 3567 , 1984; H. Kunz and R. Barthels, Angew. Chem., Int. Ed. Engl., 22 , 783, 1983), H-Lys(4-Pyoc)-OH was prepared. 33 g of H-Lys(4-Pyoc)-OH was suspended in 300 mL of 5% NaHCO ₃ . 300 mL of acetone and 52 g of Fmoc-Yrp-OSu were added to the reaction mixture. The mixture was stirred overnight at RT. The mixture was washed with ether (1 x 500 mL). 500 mL of ethyl acetate was added to the mixture. The pH of the mixture was adjusted to 2.2-2.3 with 3N HCl. The ethyl acetate layer was collected and washed with water. Organic solutions were dried over sodium sulfate. The organic solution was evaporated to dryness to give 55 g of Fmoc-Trp-Lys(4-Pyoc)-OH.

Preparation of Cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OH: 50 g Fmoc-Trp-Lys(4-Pyoc)-OH and 13 g 1-Hydroxy 100 g of Wang's resin was suspended in 700 mL of DMF solution containing benzotriazole, 2 g of 4-dimethylaminopyridine and 12 g of N,N'-diisopropylcarbodiimide. The mixture was stirred overnight at RT. The resin was collected by filtration and washed with DMF (3 x 400 mL), methanol (3 x 400 mL) and 3 x dichloromethane (400 mL). 700 mL of 20% piperidine was added to the resin. The mixture was stirred for 30 minutes. The resin was collected by filtration and washed with DMF (3 x 400 mL), methanol (3 x 400 mL) and 3 x dichloromethane (400 mL). 700 mL of DMF, 48 g of Fmoc-Arg(diAc)-OH, 13 g of 1-hydroxybenzotriazole, 35 g of triethylamine and 38 g of O-(benzotriazol-1-yl)-N,N,N',N'- Tetramethyluronium was added to the resin. The mixture was stirred at RT for 2 hours. The resin was collected by filtration and washed with DMF (3 x 400 mL), methanol (3 x 400 mL) and 3 x dichloromethane (400 mL). 700 mL of 20% piperidine was added to the resin. The mixture was stirred for 30 minutes. The resin was collected by filtration and washed with DMF (3 x 400 mL), methanol (3 x 400 mL) and 3 x dichloromethane (400 mL). 700 mL of DMF, 39 g of Fmoc-Phe-OH, 13 g of 1-hydroxybenzotriazole, 35 g of triethylamine and 38 g of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluro nium was added to the resin. The mixture was stirred at RT for 2 hours. The resin was collected by filtration and washed with DMF (3 x 400 mL), methanol (3 x 400 mL) and 3 x dichloromethane (400 mL). 700 mL of 20% piperidine was added to the resin. The mixture was stirred for 30 minutes. The resin was collected by filtration and washed with DMF (3 x 400 mL), methanol (3 x 400 mL) and 3 x dichloromethane (400 mL). 700 mL of DMF, 60 g of Fmoc-His(Fmoc)-OH, 13 g of 1-hydroxybenzotriazole, 35 g of triethylamine and 38 g of O-(benzotriazol-1-yl)-N,N,N',N'- Tetramethyluronium was added to the resin. The mixture was stirred at RT for 2 hours. The resin was recovered by filtration and DMF (
400 mL x 3), methanol (400 mL x 3) and dichloromethane (400 mL x 3). 700 mL of 20% piperidine was added to the resin. The mixture was stirred for 30 minutes. The resin was collected by filtration and washed with DMF (3 x 400 mL), methanol (3 x 400 mL) and 3 x dichloromethane (400 mL). 700 mL of DMF, 60 g of Ac-Nle-Asp(OFm)-OH, 13 g of 1-hydroxybenzotriazole, 35 g of triethylamine and 38 g of O-(benzotriazol-1-yl)-N,N,N',N '-Tetramethyluronium was added to the resin. The mixture was stirred at RT for 2 hours. The resin was collected by filtration and washed with DMF (3 x 400 mL), methanol (3 x 400 mL) and 3 x dichloromethane (400 mL). The peptidized resin was suspended in 700 mL DMF. 50 g of Mel was added to the reaction mixture. The mixture was stirred at RT for 1 hour and at 50° C. for 1 hour. The resin was collected by filtration and washed with DMF (3 x 400 mL), methanol (3 x 400 mL) and 3 x dichloromethane (400 mL). 700 mL of 30% piperidine was added to the resin. The mixture was stirred for 60 minutes. The resin was collected by filtration and washed with DMF (400 mL x 3), methanol (400 mL x 3) and dichloromethane (400 mL x 3). 700 mL of DMF, 13 g of 1-hydroxybenzotriazole, 35 g of triethylamine and 38 g of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium were added to the resin. The mixture was stirred at RT for 10 hours. The resin was collected by filtration and washed with DMF (400 mL x 3), methanol (400 mL x 3) and dichloromethane (400 mL x 3). 500 mL of trifluoroacetic acid was added to the resin and the mixture was stirred at RT for 1 hour. The resin was removed by filtration and the solution was evaporated to dryness. The residue was washed with ether (3 x 100 mL).

Preparation of Cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OCH ₂ CH ₂ N(CH ₂ CH ₃ ).HCl: 10 g Cyclo(1,6) -Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OH was dissolved in 300 mL of DMF. The mixture was cooled to 0° C. with an ice-water bath. 12 g of N,N-diethylaminoethanol, 2 g of 4-dimethylaminopyridine and 22 g of 1,3-dicyclohexylcarbodiimide were added to the reaction mixture. The reaction mixture was stirred at 0° C. for 1 hour and at RT overnight. Solids were removed by filtration and the dichloromethylene solution was washed with 5% sodium bicarbonate (1 x 500 mL) and water (1 x 100 mL). The ethyl acetate solution was dried over sodium sulfate. 2 g of HCl in dioxane (20 mL) was added to the solution. The solid was collected and washed with ether (3 x 30 mL). Yield was 8 g of final product.
Solid phase synthesis of peptide HPP/HPC

は樹脂であり；
Ｘ¹はＨ、Ｃｌ、メチル及びメトキシルから成る群から選択され；
Ｒ¹、Ｒ²・・・Ｒⁿは、Ｎ末端からＣ末端にそれぞれ１、２・・・ｎと数えられるペプチドＨＰＰ／ＨＰＣのアミノ酸の側鎖であり；
カップリング試薬は、ＨＢＴＵ／ＤＩＰＥＡ／ＨＯＢｔ、ＴＢＴＵ／ＤＩＰＥＡ／ＨＯＢｔ、ＢＯＰ／ＤＩＰＥＡ／ＨＯＢｔ、ＨＡＴＵ／ＤＩＰＥＡ／ＨＯＢｔ、ＤＩＣ／ＨＯＢ及びそれらの組み合わせから成る群から選択され；
Ｒ_Tは、置換及び非置換のアルキル基、置換及び非置換のシクロアルキル基、置換及び非置換のヘテロシクロアルキル基、置換及び非置換のアルキルオキシ基、置換及び非置換のアルケニル基、置換及び非置換のアルキニル基、置換及び非置換のアリール基、置換及び非置換のヘテロアリール基、及び上記で定義されたような構造Ｎａ，構造Ｎｂ，構造Ｎｃ，構造Ｎｄ，構造Ｎｅ，構造Ｎｆ，構造Ｎｇ，構造Ｎｈ，構造Ｎｉ，構造Ｎｊ，構造Ｎｋ，構造Ｎｌ，構造Ｎｍ，構造Ｎｎ，構造Ｎｏ，構造Ｎｐ，構造Ｎｑ，及び構造Ｎｒから成る群から選択される輸送ユニットから選択される。

スキーム３．塩化トリチル樹脂とカルボキシル基保護基としての２－（４－ニトロフェニルスルホニル）エチル基を用いたペプチドＨＰＰ／ＨＰＣの合成 The peptide HPP/HPC of the peptide was prepared using trityl chloride resin and a 2-(4-nitrophenylsulfonyl)ethyl group as a carboxyl protecting group (Scheme 3), wherein

is a resin;
X ¹ is selected from the group consisting of H, Cl, methyl and methoxyl;
R ¹ , R ² . . . R ⁿ are side chains of amino acids of the peptide HPP/HPC numbered 1, 2 .
the coupling reagent is selected from the group consisting of HBTU/DIPEA/HOBt, TBTU/DIPEA/HOBt, BOP/DIPEA/HOBt, HATU/DIPEA/HOBt, DIC/HOB and combinations thereof;
R _T is a substituted and unsubstituted alkyl group, a substituted and unsubstituted cycloalkyl group, a substituted and unsubstituted heterocycloalkyl group, a substituted and unsubstituted alkyloxy group, a substituted and unsubstituted alkenyl group, a substituted and unsubstituted unsubstituted alkynyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heteroaryl groups, and structure Na, structure Nb, structure Nc, structure Nd, structure Ne, structure Nf, structure as defined above; A transport unit selected from the group consisting of Ng, structure Nh, structure Ni, structure Nj, structure Nk, structure Nl, structure Nm, structure Nn, structure No, structure Np, structure Nq, and structure Nr.

Scheme 3. Synthesis of Peptide HPP/HPC Using Trityl Chloride Resin and 2-(4-Nitrophenylsulfonyl)ethyl Group as Carboxyl Protecting Group

As used herein, unless otherwise defined, "DCM" means dichloromethane.

Ｘ¹、Ｒ¹、Ｒ²・・・Ｒⁿ、Ｒ^T、及びカップリング試薬は上記と同義である。

スキーム４．塩化トリチル樹脂とカルボキシル基保護基としての９－フルオレニルメチル基を用いたペプチドＨＰＰ／ＨＰＣの合成 In a particular embodiment, the peptide HPP/HPC is prepared using trityl chloride resin and a 9-fluorenylmethyl group as a carboxyl protecting group (Scheme 4), wherein

X ¹ , R ¹ , R ² . . . R ⁿ , R ^T , and coupling reagent are the same as defined above.

Scheme 4. Synthesis of Peptide HPP/HPC Using Trityl Chloride Resin and 9-Fluorenylmethyl Group as Carboxyl Protecting Group

Ｒ¹、Ｒ²・・・Ｒⁿ、Ｒ^T、及びカップリング試薬は上記と同義である。

スキーム５．炭酸エステル樹脂とカルボキシル基保護基としての９－フルオレニルメチル基を用いたペプチドＨＰＰ／ＨＰＣの合成 In certain embodiments, the peptide HPP/HPC is prepared using a carbonate resin and a 9-fluorenylmethyl group as a carboxyl protecting group (Scheme 5), wherein

R ¹ , R ² . . . R ⁿ , R ^T , and coupling reagent are as defined above.

Scheme 5. Synthesis of Peptide HPP/HPC Using Carbonate Ester Resin and 9-Fluorenylmethyl Group as Carboxyl Protecting Group

Ｒ¹、Ｒ²・・・Ｒⁿ、Ｒ^T、及びカップリング試薬は上記と同義である。

スキーム６．炭酸エステル樹脂とカルボキシル基保護基としての２－（４－ニトロフェニルスルホニル）エチル基を用いたペプチドＨＰＰ／ＨＰＣの合成
実施例２．ペプチドＨＰＰ／ＨＰＣはその親薬剤に比べてヒトの皮膚を横切る高い試験管内浸透率を示した In a particular embodiment, the peptide HPP/HPC is prepared using a carbonate resin and a 2-(4-nitrophenylsulfonyl)ethyl group as a carboxyl protecting group (Scheme 6), wherein

R ¹ , R ² . . . R ⁿ , R ^T and coupling reagent are the same as defined above.

Scheme 6. Synthesis of Peptide HPP/HPC Using Carbonate Ester Resin and 2-(4-Nitrophenylsulfonyl)ethyl Group as Carboxyl Group-Protecting Group Example 2. Peptide HPP/HPC showed higher in vitro penetration across human skin compared to its parent drug

The permeability of HPPs/HPCs and their parent drugs through human skin was measured in vitro by a modified Franz cell. A Franz cell has two chambers, an upper sample chamber and a lower receiving chamber. Human skin tissue separating the upper and lower receiving chambers was isolated from the anterior and posterior thigh regions.

A test compound (2 mL of 20% in 0.2 M phosphate buffer, pH 7.4) was added to the sample chamber of the Franz cell. The receiving chamber contains 10 mL of pH 7.4 phosphate buffer (0.2 M) stirred at 600 rpm. The amount of test compound that penetrated the skin was determined by a high performance liquid chromatography (HPLC) method. The results are shown in FIG. Apparent fluxes of test compounds were calculated from the slopes of FIG. 2 and summarized in Table 1, respectively.

実施例３．ＨＰＰｓ／ＨＰＣｓの親薬剤への変換 Since the lowest detectable flux by this method is 1 μg/cm ² /hr, parent drugs exhibiting an apparent flux of 1 μg/cm ² /hr or less were considered undetectable for penetrating across skin tissue. . HPPs/HPCs of these parent compounds (e.g. enterostatin, Val-Pro-Gly-Pro-Arg (VPGPR), melanocortin II (Cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg-Trp- Lys-OH), opioid peptides (e.g., Met-enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH) was 1 μg/cm ² /hr and thus detectable for penetrating across skin tissue. However, the HPPs/HPCs had a detectable apparent flux, thus the peptide HPPs/HPCs had a higher penetration rate (340-600 fold) across skin tissue compared to their parent compounds. high).

Example 3. Conversion of HPPs/HPCs to Parent Drugs

Peptide HPPs/HPCs were rapidly converted to parent peptides or peptide-related compounds in human plasma.

実施例４．ペプチドＨＰＰｓ／ＨＰＣｓを用いた肥満の治療 Peptide HPP/HPC (20 mg) was incubated with whole blood (1 mL) at 37° C. for 30 minutes and analyzed by HPLC. The results showed that most of the peptide HPPs/HPCs were converted back to parent peptides or peptide-related compounds.

Example 4. Treatment of Obesity with Peptide HPPs/HPCs

Enterostatin [Val-Pro-Asp-Pro-Arg (VPDPR), Val-Pro-Gly-Pro-Arg (VPGPR) and Ala-Pro-Gly-Pro-Arg (APGPR)] is a procolipase after trypsin cleavage. is a pentapeptide derived from the NH ₂ -terminus of and belongs to the family of gut-brain peptides. They regulate fat intake and may be used in the treatment of obesity (Erlanson-Albertsson C, York D, Obes. Rev. 1997 Jul; 5(4): 360-72 and Sorhede M, Mei J, Erlanson-Albertsson C ., J Physiol. 87:273275, 1993). When injected intraperitoneally into overnight fasted Osborne-Mendel rats, H-Val-Pro-Asp-Pro-Arg-OH produced a dose-dependent reduction in food intake. This inhibition of feeding was observed when rats were fed a high-fat diet, but not in rats fed a high-carbohydrate, low-fat diet (Okada S. et al. Physiol Behav., 1991). Jun; 49(6): 1185-9).
Antiobesity activity of H-Val-Pro-Gly-Pro-Arg(NO ₂ )-OCH(CH ₃ ) _2.HCl in Sprague Dawley rats and DB/DB mice

H-Val-Pro-Gly-Pro-Arg(NO ₂ )-OCH(CH ₃ ) ₂ .HCl (administered transdermally, 0.3 mg/kg in rats) in Sprague Dawley (SD) rats and DB/DB mice and low) reduced food intake and body weight. The results are shown in Tables 3, 4 and 5.

In the first experiment, 40 female Sprague Dawley rats (15 weeks old, 318-346 g) were divided into 4 groups. In group A, 0.2 mL of water was administered twice daily on the back of rats for 30 days (n=10). 10 mg/kg, 1 mg/kg and 0.3 mg/kg H-Val-Pro-Gly-Pro-Arg(NO ₂ )-OCH(CH ₃ ) ₂ ·HCl was administered transdermally to the back of rats twice daily for 30 days (n=10). The results showed that H-Val-Pro-Gly-Pro-Arg(NO ₂ )-OCH(CH ₃ ) ₂ .HCl effectively reduced the body weight of rats (Table 3).

In a second experiment, 40 juvenile female Sprague Dawley (SD) rats (180-225 g) were divided into 4 groups. In group A, 0.2 mL of water was administered twice daily on the back of rats for 30 days (n=10). 10 mg/kg, 1 mg/kg and 0.3 mg/kg H-Val-Pro-Gly-Pro-Arg(NO ₂ )-OCH(CH ₃ ) ₂ ·HCl was administered transdermally on the back of rats twice daily for 30 days (n=10). The results showed that H-Val-Pro-Gly-Pro-Arg(NO ₂ )-OCH(CH ₃ ) ₂ .HCl effectively controlled overweight in juvenile rats (Table 4).

Ｓｐｒａｇｕｅ ＤａｗｌｅｙラットにおけるＨ－Ｖａｌ－Ｐｒｏ－Ｇｌｙ－Ｐｒｏ－Ａｒｇ（ｄｉＡｃ）－ＯＣＨ ₂ ＣＨ ₂ ＣＨ ₂ ＣＨ ₃ ・ＨＣｌの抗肥満 In a third experiment, 40 obese female DB/DB mice (SLAC/DB/DB mice, 16 weeks old, 55-60 g) were divided into 4 groups. In group A, 0.1 mL of water was administered to the back of mice twice daily for 30 days (n=10). 15 mg/kg, 1.5 mg/kg and 0.5 mg/kg H-Val-Pro-Gly-Pro-Arg(NO ₂ )-OCH in 0.1 mL water in groups B, C and D, respectively. (CH ₃ ) ₂ .HCl was administered transdermally on the back of mice twice daily for 30 days (n=10). The results showed that H-Val-Pro-Gly-Pro-Arg(NO ₂ )-OCH(CH ₃ ) ₂ .HCl effectively reduced body weight and blood glucose levels in obese mice (Table 5).

Antiobesity of H-Val-Pro-Gly-Pro-Arg(diAc)-OCH ₂ CH ₂ CH ₂ CH ₃ .HCl in Sprague Dawley Rats

H-Val-Pro-Gly-Pro-Arg(diAc)-OCH ₂ CH ₂ CH ₂ CH ₃ .HCl (administered transdermally, as low as 0.3 mg/kg in rats) was effective in SD rats and DB/DB It reduced food intake and body weight in mice. The results are shown in Tables 6, 7 and 8.

In the first experiment, 40 female Sprague Dawley (SD) rats (15 weeks old, 315-340 g) were divided into 4 groups. In group A, 0.2 mL of water was administered twice daily on the back of rats for 30 days (n=10). 10 mg/kg, 1 mg/kg and 0.3 mg/kg H-Val-Pro-Gly-Pro-Arg(diAc)-OCH ₂ CH ₂ in 0.2 mL water for groups B, C and D, respectively. CH ₂ CH ₃ .HCl was administered transdermally to the back of rats twice daily for 30 days (n=10). The results showed that H-Val-Pro-Gly-Pro-Arg(diAc)-OCH ₂ CH ₂ CH ₂ CH ₃ .HCl effectively reduced the body weight of rats (Table 6).

In a second experiment, 40 juvenile female Sprague Dawley (SD) rats (180-230 g) were divided into 4 groups. In group A, 0.2 mL of water was administered twice daily on the back of rats for 30 days (n=10). 10 mg/kg, 1 mg/kg and 0.3 mg/kg H-Val-Pro-Gly-Pro-Arg(diAc)-OCH ₂ CH ₂ in 0.2 mL water for groups B, C and D, respectively. CH ₂ CH ₃ .HCl was administered transdermally to the back of rats twice daily for 30 days (n=10). The results showed that H-Val-Pro-Gly-Pro-Arg(diAc)-OCH ₂ CH ₂ CH ₂ CH ₃ .HCl effectively controlled overweight in juvenile rats (Table 7).

Ｓｐｒａｇｕｅ ＤａｗｌｅｙラットにおけるＨ－Ａｌａ－Ｐｒｏ－Ｇｌｙ－Ｐｒｏ－Ａｒｇ（ＮＯ ₂ ）－ＯＣＨ ₂ ＣＨ ₂ ＣＨ ₂ ＣＨ ₃ ・ＨＣｌの抗肥満 In a third experiment, 40 obese female DB/DB mice (SLAC/DB/DB mice, 16 weeks old, 55-60 g) were divided into 4 groups. In group A, 0.1 mL of water was administered to the back of mice twice daily for 30 days (n=10). 15 mg/kg, 1.5 mg/kg and 0.5 mg/kg H-Val-Pro-Gly-Pro-Arg(diAc)-OCH ₂ in 0.1 mL water for groups B, C and D, respectively. CH ₂ CH ₂ CH ₃ .HCl was administered transdermally on the back of mice twice daily for 30 days (n=10). The results showed that H-Val-Pro-Gly-Pro-Arg(diAc)-OCH ₂ CH ₂ CH ₂ CH _3.HCl effectively reduced body weight and blood glucose levels in obese mice (Table 8). .

Antiobesity of H-Ala-Pro-Gly-Pro-Arg(NO ₂ )-OCH ₂ CH ₂ CH ₂ CH ₃ .HCl in Sprague Dawley Rats

H-Ala-Pro-Gly-Pro-Arg(NO ₂ )-OCH ₂ CH ₂ CH ₂ CH ₃ .HCl (administered transdermally, as low as 0.3 mg/kg in rats) was effective in SD rats and DB/ Food intake and body weight were reduced in DB mice. The results are shown in Tables 9, 10 and 11.

In the first experiment, 40 female Sprague Dawley (SD) rats (15 weeks old, 320-345 g) were divided into 4 groups. In group A, 0.2 mL of water was administered twice daily on the back of rats for 30 days (n=10). 10 mg/kg, 1 mg/kg and 0.3 mg/kg H-Ala-Pro-Gly-Pro-Arg(NO ₂ )-OCH ₂ CH in 0.2 mL water for groups B, C and D, respectively. ₂ CH ₂ CH ₃ .HCl was administered transdermally to the back of rats twice daily for 30 days (n=10). The results showed that H-Ala-Pro-Gly-Pro-Arg(NO ₂ )-OCH ₂ CH ₂ CH ₂ CH ₃ ·HCl effectively reduced the body weight of rats (Table 9).

In a second experiment, 40 juvenile female Sprague Dawley (SD) rats (182-223 g) were divided into 4 groups. In group A, 0.2 mL of water was administered twice daily on the back of rats for 30 days (n=10). 10 mg/kg, 1 mg/kg and 0.3 mg/kg H-Ala-Pro-Gly-Pro-Arg(NO ₂ )-OCH ₂ CH in 0.2 mL water for groups B, C and D, respectively. ₂ CH ₂ CH ₃ .HCl was administered transdermally to the back of rats twice daily for 30 days (n=10). The results showed that H-Ala-Pro-Gly-Pro-Arg(NO ₂ )-OCH ₂ CH ₂ CH ₂ CH _3.HCl effectively controlled overweight in juvenile rats (Table 10). .

Ｓｐｒａｇｕｅ ＤａｗｌｅｙラットにおけるＨ－Ｖａｌ－Ｐｒｏ－Ａｓｐ（ＯＥｔ）－Ｐｒｏ－Ａｒｇ（ＮＯ ₂ ）－ＯＣＨ ₂ ＣＨ ₂ ＣＨ ₂ ＣＨ ₃ ・ＨＣｌの抗肥満 In a third experiment, 40 obese female DB/DB mice (SLAC/DB/DB mice, 16 weeks old, 53-61 g) were divided into 4 groups. In group A, 0.1 mL of water was administered to the back of mice twice daily for 30 days (n=10). 15 mg/kg, 1.5 mg/kg and 0.5 mg/kg H-Ala-Pro-Gly-Pro-Arg(NO ₂ )-OCH in 0.1 mL water for groups B, C and D, respectively. ₂ CH ₂ CH ₂ CH ₃ .HCl was administered transdermally on the back of mice twice daily for 30 days (n=10). The results showed that H-Ala-Pro-Gly-Pro-Arg(NO ₂ )-OCH ₂ CH ₂ CH ₂ CH _3.HCl effectively reduced body weight and blood glucose levels in obese mice (Table 11). ).

Antiobesity of H-Val-Pro-Asp(OEt)-Pro-Arg(NO ₂ )-OCH ₂ CH ₂ CH ₂ CH _3.HCl in Sprague Dawley Rats

H-Val-Pro-Asp(OEt)-Pro-Arg(NO ₂ )-OCH ₂ CH ₂ CH ₂ CH ₃ .HCl (administered transdermally, 0.3 mg/day in rats) in SD rats and DB/DB mice. kg) reduced food intake and body weight. The results are shown in Tables 12, 13 and 14.

In the first experiment, 40 female Sprague Dawley (SD) rats (15 weeks old, 320-350 g) were divided into 4 groups. In group A, 0.2 mL of water was administered twice daily on the back of rats for 30 days (n=10). 10 mg/kg, 1 mg/kg and 0.3 mg/kg H-Val-Pro-Asp(OEt)-Pro-Arg(NO ₂ )- in 0.2 mL water in Groups B, C and D, respectively. OCH ₂ CH ₂ CH ₂ CH ₃ .HCl was administered transdermally to the back of rats twice daily for 30 days (n=10). The results showed that H-Val-Pro-Asp(OEt)-Pro-Arg(NO ₂ )-OCH ₂ CH ₂ CH ₂ CH ₃ ·HCl effectively reduced the body weight of rats (Table 12). .

In a second experiment, 40 juvenile female Sprague Dawley (SD) rats (185-220 g) were divided into 4 groups. In group A, 0.2 mL of water was administered twice daily on the back of rats for 30 days (n=10). 10 mg/kg, 1 mg/kg and 0.3 mg/kg H-Val-Pro-Asp(OEt)-Pro-Arg(NO ₂ )- in 0.2 mL water in Groups B, C and D, respectively. OCH ₂ CH ₂ CH ₂ CH ₃ .HCl was administered transdermally to the back of rats twice daily for 30 days (n=10). The results showed that H-Val-Pro-Asp(OEt)-Pro-Arg(NO ₂ )-OCH ₂ CH ₂ CH ₂ CH ₃ ·HCl effectively controlled overweight in juvenile rats ( Table 13).

実施例５．ペプチドＨＰＰｓ／ＨＰＣｓによる勃起不全（ＥＤ）及び女性の性的不能の治療 In a third experiment, 40 obese female DB/DB mice (SLAC/DB/DB mice, 16 weeks old, 53-61 g) were divided into 4 groups. In group A, 0.1 mL of water was administered to the back of mice twice daily for 30 days (n=10). 15 mg/kg, 1.5 mg/kg and 0.5 mg/kg H-Val-Pro-Asp(OEt)-Pro-Arg(NO ₂ )-OCH ₂ CH ₂ CH ₂ CH ₃ .HCl was administered subcutaneously on the back of mice twice daily for 30 days (n=10). The results showed that H-Val-Pro-Asp(OEt)-Pro-Arg(NO ₂ )-OCH ₂ CH ₂ CH ₂ CH _3.HCl effectively reduced body weight and blood glucose level in obese mice. (Table 14).

Example 5. Treatment of erectile dysfunction (ED) and female impotence with peptide HPPs/HPCs

Melanocortin II is a cyclic lactam peptide, Cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-OH. It is Palatin's (AMEX:PTN) novel drug candidate for the treatment of male and female impotence. For the first time in a new class of therapies called melanocortin agonists, Melanocortin II effectively treats erectile dysfunction (ED) and female impotence without the cardiovascular effects seen with currently available ED drugs. shown to be promising for Melanocortin II does not act directly on the vasculature, but through mechanisms involving the central nervous system. As a result, they offer significant safety and efficacy benefits over currently available products.

HPP/HPC of melanocortin II diffuses through human skin at a very high rate (approximately 0.3-0.5 mg/hr/cm2) to treat erectile dysfunction or enhance sexual arousal in women, most Provided a method without side effects.

Cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OCH ₂ at 2 mg/kg in 0.2 mL of pH 7.0 phosphate buffer (0.1 M) CH ₂ N(CH ₂ CH ₃ ) ₂ .HCl (peptide A) was applied to the backs of male rats (Group A-1, 30 rats) once a day for 5 days. The same dose of Cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(NO ₂ )-Trp-Lys-OCH ₂ CH ₂ N(CH ₂ CH ₃ ) _2.HCl (peptide B) was Another group of rats (B-1 group, 30 rats) was applied to the back. A control group of rats received no drug treatment. The results showed a 5-fold increase in seduction behavior and a 3-fold increase in mating behavior for the A-1 group compared to the negative control. A 6-fold increase in seduction behavior and a 3-fold increase in mating behavior were observed for the B-1 group compared to the control group (Table 15).

Ｘ：１日１回５日間背中にてＨＰＰ／ＨＰＣ（ｐＨ７．０のリン酸緩衝液（０．１Ｍ）０．２ｍＬ中の２ｍｇ／ｋｇ）で処理した。
実施例６．エンケファリン及び関連化合物のＨＰＰｓ／ＨＰＣｓによる苦痛抑制 2 mg/kg Peptide A and Peptide B in 0.2 mL of pH 7.0 phosphate buffer (0.1 M) once daily on the back of both male (30) and female (30) rats for 5 days. applied. Control rats received no drug treatment. The results showed a 6-fold increase in seduction behavior and a 5-fold increase in mating behavior in both the A-2 and B-2 groups compared to the control group (Table 15).

X: Treated with HPP/HPC (2 mg/kg in 0.2 mL of phosphate buffer (0.1 M) pH 7.0) on the back once daily for 5 days.
Example 6. Distress suppression by HPPs/HPCs of enkephalins and related compounds

Opioid peptides (e.g., Met-Enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH), Leu-Enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH), H-Tyr-D-Ala -Gly-N-Me-Phe-Met(O)-OL and H-Tyr-D-Ala-Gly-Phe-Leu-OH) exert morphine-like analgesic effects. When the acid solution was intraperitoneally administered to the mice, the number of pain caused was counted and the inhibition rate was calculated based on the control group. HCl.H-Tyr(Ac)-D-Ala-Gly-Phe-Leu-OCH ₂ (CH ₂ ) ₄ CH ₃ (10 mg/kg, B), Ac-Tyr(Ac)-D-Ala-Gly-Phe - Leu-OCH ₂ CH ₂ N(CH ₂ CH ₃ ).HCl (10 mg/kg, C) and HCl.H-Tyr(Ac)-D-Ala-Gly-Phe-Met(O)-OL (10 mg/kg) kg, D) was administered percutaneously to the neck of mice, and 30 minutes later, an acidic solution was administered. Group A was the control group. The results are shown in Table 16.

本発明のまた別の態様は、以下のとおりであってもよい。
〔１〕ペプチド又はペプチド関連化合物の高浸透性組成物であって、
（ａ）機能ユニットと
（ｂ）リンカーと
（ｃ）輸送ユニットを含み、
機能ユニットはリンカーを介して輸送ユニットに共有結合し、
機能ユニットはペプチド又はペプチド関連化合物の部分を含み、
輸送ユニットはプロトン化可能なアミン基を含み、
リンカーは、高浸透性組成物が１以上の生体バリアを横切った後、切断されることが可能である化学結合を含む、高浸透性組成物。
〔２〕化学結合が、共有結合、エーテル結合、チオエーテル結合、エステル結合、チオエステル結合、炭酸結合、カルバミン酸結合、リン酸結合、及びオキシム結合から成る群から選択される前記〔１〕に記載の高浸透性組成物。
〔３〕切断可能な結合の切断の際、ペプチド又はペプチド関連化合物の部分がペプチド又はペプチド関連化合物に変換される前記〔１〕に記載の高浸透性組成物。
〔４〕機能ユニットが、ペプチド又はペプチド関連化合物の部分の親油性誘導体を含む前記〔１〕に記載の高浸透性組成物。
〔５〕親油性誘導体が、炭酸エステル、アミド、カルバメート、Ｎ－マンニッヒ塩基、エーテル、チオエーテル、チオエステル、リン酸塩、オキシム及びイミンから成る群から選択される前記〔４〕に記載の高浸透性組成物。
〔６〕ペプチド又はペプチド関連化合物が、ペプチド、ペプチド代謝体、又はペプチド又はペプチド代謝体に代謝され得る剤、及びそれらの類似体から成る群から選択される前記〔１〕に記載の高浸透性組成物。
〔７〕プロトン化可能なアミン基が、置換及び非置換の１級アミン基、置換及び非置換の２級アミン基、並びに置換及び非置換の３級アミン基から成る群から選択される前記〔１〕に記載の高浸透性組成物。
〔８〕プロトン化可能なアミン基が、固有である、又は構造Ｎａ，構造Ｎｂ，構造Ｎｃ，構造Ｎｄ，構造Ｎｅ，構造Ｎｆ，構造Ｎｇ，構造Ｎｈ，構造Ｎｉ，構造Ｎｊ，構造Ｎｋ，構造Ｎｌ，構造Ｎｍ，構造Ｎｎ，構造Ｎｏ，構造Ｎｐ，構造Ｎｑ，及び構造Ｎｒ：

から成る群から選択され、その立体異性体及び薬学上許容可能なその塩を含み、式中、
Ｒ ₁₁ ～Ｒ ₁₆ は、独立して、無、Ｈ、ＣＨ ₂ ＣＯＯＲ ₁₁ 、置換及び非置換のアルキル、置換及び非置換のシクロアルキル、置換及び非置換のヘテロシクロアルキル、置換及び非置換のアリール、置換及び非置換のヘテロアリール、置換及び非置換のアルコキシ、置換及び非置換のアルキルチオ、置換及び非置換のアルキルアミノ、置換及び非置換のパーフルオロアルキル、置換及び非置換のアルキルハライドから成る群から選択され、その際、炭素又は水素はさらに独立して、Ｏ、Ｓ、Ｐ、ＮＲ ₁₁ 又はそのほかの薬学上許容可能な基によって置き換えられてもよい前記〔７〕に記載の高浸透性組成物。
〔９〕以下の化学構造

構造Ｌ－１
を有する高浸透組成物であって、その立体異性体及び薬学上許容可能なその塩を含み、式中、
Ｆは、構造Ｆ－１：

を有するペプチド又はペプチド関連化合物の部分を含み、
各Ａ ₁ ～Ａ _m は、は独立して、２－ナフチルアラニン、置換及び非置換のアルキル、置換及び非置換のシクロアルキル、置換及び非置換のヘテロシクロアルキル、置換及び非置換のアルコキシ、置換及び非置換のアルケニル、置換及び非置換のアルキニル、置換及び非置換のアルキルチオ、置換及び非置換のアルキルアミノ、置換及び非置換のパーフルオロアルキル、置換及び非置換のアルキルハライド、置換及び非置換のアリール、置換及び非置換のヘテロアリールの残基、構造Ａ及び構造Ｂ：

構造Ａ

構造Ｂ
から成る群から選択され；
各Ａ ₁ ～Ａ _m の各ｐは独立して選択される整数であり；
各Ａ ₁ ～Ａ _m の各炭素におけるＺ _A-1 、各Ａ ₁ ～Ａ _m についてのＺ _A-2 、Ｚ _NT 、Ｚ _CT-1 及びＺ _CT-2 は独立して、Ｈ、ＣＨ ₃ 、Ｃ ₂ Ｈ _5、 Ｃ ₃ Ｈ ₇ 、ＣＦ ₃ 、Ｃ ₂ Ｆ ₅ 、Ｃ ₃ Ｆ ₇ 、置換及び非置換のアルキル、置換及び非置換のシクロアルキル、置換及び非置換のヘテロシクロアルキル、置換及び非置換のアルキルオキシ、置換及び非置換のアルケニル、置換及び非置換のアルキニル、置換及び非置換のアリール、置換及び非置換のヘテロアリール基、置換及び非置換のパーフルオロアルキル、並びに、置換及び非置換のアルキルハライドから成る群から選択され；
各Ａ ₁ ～Ａ _m の各炭素におけるＲ _A 、各Ａ ₁ ～Ａ _m の各炭素におけるＲ _B 、Ｒ _NT 及びＲ _CT は、置換及び非置換のイミダゾリル、置換及び非置換のグアニジノ、置換及び非置換のカルボキシル、置換及び非置換のカルボキサミド、置換及び非置換のアルキル、置換及び非置換のシクロアルキル、置換及び非置換のヘテロシクロアルキル、置換及び非置換のアルコキシ、置換及び非置換のアルキルチオ、置換及び非置換のアルキルアミノ、置換及び非置換のアルキルカルボニル、置換及び非置換のパーフルオロアルキル、置換及び非置換のアルキルハライド、置換及び非置換のアリール、並びに置換及び非置換のヘテロアリールの基から成る群から選択され；
Ａ ₁ ～Ａ _m のｐが２以上の整数である場合、各炭素上のＲ _A 又はＲ _B は、同一であっても、異なっていてもよく、各炭素上のＺ _A-1 は同一であっても、異なっていてもよく；
ペプチド鎖におけるアミノ官能基及びカルボキシ官能基はさらにラクタム架橋を形成してもよく；
チオール基はさらにジスルフィド架橋を形成してもよく；
各Ａ ₁ ～Ａ _m のＴ _B 、Ｔ _C 及びＴ _N は独立して、無、Ｈ、置換及び非置換のアルキル、置換及び非置換のシクロアルキル、置換及び非置換のヘテロシクロアルキル、置換及び非置換のアルキルオキシ、置換及び非置換のアルケニル、置換及び非置換のアルキニル、置換及び非置換のアリール、置換及び非置換のヘテロアリール、構造Ｎａ，構造Ｎｂ，構造Ｎｃ，構造Ｎｄ，構造Ｎｅ，構造Ｎｆ，構造Ｎｇ，構造Ｎｈ，構造Ｎｉ，構造Ｎｊ，構造Ｎｋ，構造Ｎｌ，構造Ｎｍ，構造Ｎｎ，構造Ｎｏ，構造Ｎｐ，構造Ｎｑ，及び構造Ｎｒ：

から成る群から選択され、
各Ｒ ₁₁ ～Ｒ ₁₆ は、独立して、無、Ｈ、ＣＨ ₂ ＣＯＯＲ ₁₁ 、置換及び非置換のアルキル、置換及び非置換のシクロアルキル、置換及び非置換のヘテロシクロアルキル、置換及び非置換のアリール、置換及び非置換のヘテロアリール、置換及び非置換のアルコキシ、置換及び非置換のアルキルチオ、置換及び非置換のアルキルアミノ、置換及び非置換のパーフルオロアルキル、置換及び非置換のアルキルハライドから成る群から選択され、その際、炭素又は水素はさらに独立して、Ｏ、Ｓ、Ｐ、ＮＲ ₁₁ 又はそのほかの薬学上許容可能な基によって置き換えられてもよく；
各Ａ ₁ ～Ａ _m のＬ _1B 、Ｌ _1C 及びＬ _1N は、無、Ｏ、Ｓ、－Ｎ（Ｌ ₃ ）－、－Ｎ（Ｌ ₃ ）－ＣＨ ₂ －Ｏ、－Ｎ（Ｌ ₃ ）－ＣＨ ₂ －Ｎ（Ｌ ₅ ）－、－Ｏ－ＣＨ ₂ －Ｏ－、－Ｏ－ＣＨ（Ｌ ₃ ）－Ｏ及び－Ｓ－ＣＨ（Ｌ ₃ ）－Ｏ－から成る群から選択され：
各Ａ ₁ ～Ａ _m のＬ _2B 、Ｌ _2C 及びＬ _2N は、無、Ｏ、Ｓ、－Ｎ（Ｌ ₃ ）－、－Ｎ（Ｌ ₃ ）－ＣＨ ₂ －Ｏ、－Ｎ（Ｌ ₃ ）－ＣＨ ₂ －Ｎ（Ｌ ₅ ）－、－Ｏ－ＣＨ ₂ －Ｏ－、－Ｏ－ＣＨ（Ｌ ₃ ）－Ｏ、－Ｓ－ＣＨ（Ｌ ₃ ）－Ｏ－、－Ｏ－Ｌ ₃ －、－Ｎ－Ｌ ₃ －、－Ｓ－Ｌ ₃ －、－Ｎ（Ｌ ₃ ）－Ｌ ₅ －及びＬ ₃ から成る群から選択され：
各Ａ ₁ ～Ａ _m 、Ｌ _4C 及びＬ _4N のＬ _4B は独立して、無、Ｃ＝Ｏ、Ｃ＝Ｓ、

及び

から成る群から選択され：
各Ｌ _1B 、Ｌ _1C 、Ｌ _1N 、Ｌ _2B 、Ｌ _2C 、Ｌ _2N 、Ｌ _4B 、Ｌ _4C 及びＬ _4N について、Ｌ ₃ 及びＬ ₅ は、独立して、無、Ｈ、ＣＨ ₂ ＣＯＯＬ ₆ 、置換及び非置換のアルキル基、置換及び非置換のシクロアルキル基、置換及び非置換のヘテロシクロアルキル基、置換及び非置換のアリール、置換及び非置換のヘテロアリール、置換及び非置換のアルコキシ、置換及び非置換のアルキルチオ、置換及び非置換のアルキルアミノ、置換及び非置換のパーフルオロアルキル、置換及び非置換のアルキルハライドから成る群から選択され、その際、炭素又は水素はさらに独立して、Ｏ、Ｓ、Ｐ、ＮＬ ₃ 又はそのほかの薬学上許容可能な基によって置き換えられてもよく；
Ｌ ₆ は、Ｈ、ＯＨ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、置換及び非置換のアルキル基、置換及び非置換のシクロアルキル基、置換及び非置換のヘテロシクロアルキル基、置換及び非置換のアリール、置換及び非置換のヘテロアリール、置換及び非置換のアルコキシ、置換及び非置換のアルキルチオ、置換及び非置換のアルキルアミノ、置換及び非置換のパーフルオロアルキル、置換及び非置換のアルキルハライドから成る群から選択され、その際、炭素又は水素はさらに独立して、Ｏ、Ｓ、Ｎ、Ｐ（Ｏ）ＯＬ ₆ 、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＬ ₆ 、ＣＬ ₆ Ｌ ₇ 、アリール、ヘテロアリール又は環状の基によって置き換えられてもよく；
Ｌ ₇ は、Ｈ、ＯＨ、Ｃｌ、Ｆ、Ｂｒ、Ｉ、置換及び非置換のアルキル基、置換及び非置換のシクロアルキル基、置換及び非置換のヘテロシクロアルキル基、置換及び非置換のアリール、置換及び非置換のヘテロアリール、置換及び非置換のアルコキシ、置換及び非置換のアルキルチオ、置換及び非置換のアルキルアミノ、置換及び非置換のパーフルオロアルキル、置換及び非置換のアルキルハライドから成る群から選択され、その際、炭素又は水素はさらに独立して、Ｏ、Ｓ、Ｎ、Ｐ（Ｏ）ＯＬ ₆ 、ＣＨ＝ＣＨ、Ｃ≡Ｃ、ＣＨＬ ₆ 、ＣＬ ₆ Ｌ ₇ 、アリール、ヘテロアリール又は環状の基によって置き換えられてもよい、
高浸透性組成物。
〔１０〕ペプチドが、エンテロスタチン、メラノコルチンＩＩ及びオピオイドペプチドから成る群から選択される前記〔９〕に記載の高浸透性組成物。
〔１１〕図１に示すような構造２、構造３、構造４、構造５、構造６、構造７、構造８、構造９、構造１０、構造１１、構造１２、構造１３、構造１４、構造１５、構造１６、構造１７、構造１８、構造１９、構造２０、構造２１、構造２２、構造２３、構造２４、構造２５、構造２６、構造２７、構造２８、構造３７、構造３８、構造３９、構造４０、構造４１、構造４２、構造４３、構造４４、構造４５、構造４６、構造４７、構造４８、構造４９、構造５０、構造５１、構造５２、構造５３、構造５４、構造５５、構造５６、構造５７、構造５８、構造５９、構造６０、構造６１、構造６２、構造６３、構造６４、構造６５、構造６６、構造６７、構造６８、構造６９、構造７０、構造７１、構造７２、構造７３、構造７４、構造７５、構造７６、構造７７、構造７８、構造７９、構造８０、構造８１、構造８２、構造８３、構造８４、構造８５、構造８６、構造８７、構造８８、構造８９、構造９０、構造９１、構造９２、構造９３、構造９４、構造９５、構造９６、構造９７、構造９８、構造９９、構造１００、構造１０１、構造１０２、構造１０３、構造１０４、構造１０５、構造１０６、構造１０７、構造１０８、構造１０９、構造１１０、構造１１１、構造１１２、構造１１３、構造１１４、構造１１５、構造１１６、構造１１７、構造１１８、構造１１９、構造１２０、構造１２１、構造１２２、構造１２３、構造１２４、構造１２５、構造１２６、構造１２７、構造１２８、構造１３７、構造１３８、構造１３９、構造１４０、構造１４１、構造１４２、構造１４３、構造１４４、構造１４５、構造１４６、構造１４７、構造１４８、構造１４９、構造１５０、構造１５１、構造１５２、構造１５３、構造１５４、構造１５５、構造１５６、構造１５７、構造１５８、構造１５９、構造１６０、構造１６１、構造１６２、構造１６３、構造１６４、構造１６５、構造１６６、構造１６７、構造１６８、構造１６９、構造１７０、構造１７１、構造１７２、構造１７３、構造１７４、構造１７５、構造１７６、構造１７７、構造１７８、構造１７９、構造１８０、構造１８１、構造１８２、構造１８３、構造１８４、構造１８５、構造１８６、構造１８７、構造１８８、構造１８９、構造１９０、構造１９１、構造１９２、構造１９３、構造１９４、構造１９５、構造１９６、構造１９７、構造１９８、構造１９９、構造２００、構造２０１、構造２０２、構造２０３、構造２０４、構造２０５、構造２０６、構造２０７、構造２０８、構造２０９、構造２１０、構造２１１、構造２１２、構造２１３、構造２１４、構造２１５、構造２１６、構造２１７、構造２１８、構造２１９、構造２２０、構造２２１、構造２２２、構造２２３、構造２２４、構造２２５、構造２２６、構造２２７、構造２２８、構造２３７、構造２３８、構造２３９、構造２４０、構造２４１、構造２４２、構造２４３、構造２４４、構造２４５、構造２４６、構造２４７、構造２４８、構造２４９、構造２５０、構造２５１、構造２５２、構造２５３、構造２５４、構造２５５、構造２５６、構造２５７、構造２５８、構造２５９、構造２６０、構造２６１、構造２６２、構造２６３、構造２６４、構造２６５、構造２６６、構造２６７、構造２６８、構造２６９、構造２７０、構造２７１、構造２７２、構造２７３、構造２７４、構造２７５、構造２７６、構造２７７、構造２７８、構造２７９、構造２８０、構造２８１、構造２８２、構造２８３、構造２８４、構造２８５、構造２８６、構造２８７、構造２８８、構造２８９、構造２９０、構造２９１、構造２９２、構造２９３、構造２９４、構造２９５、構造２９６、構造２９７、構造２９８、構造２９９、構造３００、構造３０１、構造３０２、構造３０３、構造３０４、構造３０５、構造３０６、構造３０７、構造３０８、構造３０９、構造３１０、構造３１１、構造３１２、構造３１３、構造３１４、構造３１５、構造３１６、構造３１７、構造３１８、構造３１９、構造３２０、構造３２１、構造３２２、構造３２３、構造３２４、構造３２５、構造３２６、構造３２７、構造３２８、構造３３７、構造３３８、構造３３９、構造３４０、構造３４１、構造３４２、構造３４３、構造３４４及び構造３４５の構造から成る群から選択される構造を含み、その立体異性体及び薬学上許容可能なその塩を含み、式中、
Ｒは、Ｈ、置換及び非置換のアルキル基、置換及び非置換のシクロアルキル基、置換及び非置換のヘテロシクロアルキル基、置換及び非置換のアルコキシ、置換及び非置換のアルキルチオ、置換及び非置換のアルキルアミノ、置換及び非置換のアリール、並びに置換及び非置換のヘテロアリールの残基から成る群から選択され；
Ｘ、Ｘ ₄ 、Ｘ ₅ 、Ｘ ₆ 、Ｘ ₇ 、Ｘ ₈ 、Ｘ ₉ 、Ｘ ₁₀ 、Ｘ ₂₁ 、Ｘ ₂₂ 、Ｘ ₂₃ 、Ｘ ₂₄ 、Ｘ ₂₅ 、Ｘ ₂₆ 及びＸ ₂₇ は独立して、Ｃ＝Ｏ、Ｃ＝Ｓ、ＣＯＯ、ＣＳＯ、ＣＨ ₂ ＯＣＯ、ＣＯＯＣＨ ₂ ＯＣＯ、ＣＯＣＨ ₂ ＯＣＯ、ＣＨ ₂ －Ｏ－ＣＨ（ＣＨ ₂ ＯＲ ₄ ） ₂ 、ＣＨ ₂ －Ｏ－ＣＨ（ＣＨ ₂ ＯＣＯＲ ₄ ） ₂ 、ＳＯ ₂ 、ＰＯ（ＯＲ）、ＮＯ、Ｏ、Ｓ、ＮＲ ₅ 及び無から成る群から選択され；
Ｒ ₁ 、Ｒ ₂ 、Ｒ ₄ 、Ｒ ₅ 、Ｒ _6、 Ｒ ₇ 、Ｒ ₈ 、Ｒ ₉ 、Ｒ ₁₀ 、Ｒ ₂₁ 、Ｒ ₂₂ 、Ｒ ₂₃ 、Ｒ _24、 Ｒ ₂₅ 、Ｒ ₂₆ 及びＲ ₂₇ は独立して、Ｈ、Ｏ、ＮＯ ₂ 、置換及び非置換のアルキル基、置換及び非置換のシクロアルキル基、置換及び非置換のヘテロシクロアルキル基、置換及び非置換のアルコキシ、置換及び非置換のアルキルチオ、置換及び非置換のアルキルアミノ、置換及び非置換のアルケニル、置換及び非置換のアルキニル、置換及び非置換のアリール、並びに置換及び非置換のヘテロアリールの残基から成る群から選択され；
Ａｒは、フェニル、２’－ナフチル、４－ヨードフェニル、置換及び非置換のアリール、並びに置換及び非置換のヘテロアリールの残基から成る群から選択され；
ＨＡは、無、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硝酸、硫酸、重硫酸、リン酸、亜リン酸、ホスホン酸、イソニコチン酸、酢酸、乳酸、サリチル酸、クエン酸、酒石酸、パントテン酸、重酒石酸、アスコルビン酸、コハク酸、マレイン酸、ゲンチシン酸、フマル酸、グルコン酸、グルカロン酸、糖酸、蟻酸、安息香酸、グルタミン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、又はパモ酸から成る群から選択される
前記〔９〕の高浸透性組成物。
〔１２〕構造１ａ、構造１ｂ、構造１ｃ、構造１ｄ、構造１ｅ、構造１ｆ、構造１ｇ、及び構造１ｈから成る群から選択される構造を含み、

構造１ａ

構造１ｂ

構造１ｃ

構造１ｄ

構造１ｅ

構造１ｆ

構造１ｇ

構造１ｈ
その立体異性体及び薬学上許容可能なその塩を含み、式中、
Ｘ ₄ 、Ｘ ₅ 、Ｘ ₆ 、Ｘ ₇ 、Ｘ ₈ 、Ｘ ₉ 、Ｒ ₄ 、Ｒ ₅ 、Ｒ _6、 Ｒ ₇ 、Ｒ ₈ 、Ｒ ₉ 及びＨＡは前記〔１１〕と同義である前記〔９〕の高浸透性組成物。
〔１３〕前記〔９〕に記載の高浸透性組成物と薬学上許容可能なキャリアを含む医薬組成物。
〔１４〕薬学上許容可能なキャリアが極性である前記〔１３〕に記載の医薬組成物。
〔１５〕薬学上許容可能なキャリアが、アルコール、アセトン、エステル、水及び水性溶液から成る群から選択される前記〔１３〕に記載の医薬組成物。
〔１６〕前記〔１３〕に記載の医薬組成物を生体バリアに投与することを含む、生体バリアに浸透させる方法。
〔１７〕所望の特性についてペプチド又はペプチド関連化合物のＨＰＰをスクリーニングする方法であって、以下の工程：
（１）リンカーを介して、ペプチド又はペプチド関連化合物を含む機能ユニットを輸送ユニットに共有結合させて試験組成物を形成することと；
（２）生物対象又は生体バリアに試験組成物を投与することと；
（３）試験組成物が所望の特性を有するかどうかを判定することを
含む方法。
〔１８〕所望の特性が
（１）生体バリアに浸透する試験組成物の能力；
（２）親薬剤又は活性剤に変換する試験組成物の能力；
（３）試験組成物の浸透率；
（４）試験組成物の効率、及び
（５）試験組成物の有効性
から成る群から選択される前記〔１７〕に記載の方法。
〔１９〕生物対象における状態を診断する方法であって、以下の工程：
（１）生物対象に前記〔９〕に記載の組成物を投与することと；
（２）生物対象において組成物の存在、位置又は量を検出することと；
（３）生物対象において状態を検出することを
含む方法。
〔２０〕組成物が標識される前記〔１９〕に記載の方法。
〔２１〕生物対象における状態を診断する方法であって、以下の工程：
（１）生物対象に前記〔１３〕に記載の組成物を投与することと；
（２）生物対象において組成物の存在、位置又は量を検出することと；
（３）生物対象において状態を検出することを
含む方法。
〔２２〕組成物が標識される前記〔２１〕に記載の方法。
〔２３〕生物対象における状態を治療する方法であって、前記〔９〕に記載の高浸透性組成物又は前記〔１３〕に記載の医薬組成物を生物対象に投与することを含む方法。
〔２４〕状態が、疼痛、外傷、炎症関連の状態、微生物関連の状態、神経ペプチド関連の状態、ホルモン関連の状態、腫瘍、異常な血圧、肥満、脳の傷害、アレルギー、男性及び女性の性的不能、転移、及びそのほかの、ツフトシン、分娩前、分娩後、抗ＡＤ活性、抗利尿活性、カルシウム恒常性、メラニン形成細胞、ホルモン放出、血小板凝集、ＣＮＳの活動、及び貪食作用に関連する状態から成る群から選択される前記〔２３〕に記載の方法。
〔２５〕ホルモン関連の状態が、閉経、骨疾患、成長ホルモンの欠損、甲状腺機能亢進、甲状腺機能低下、代謝性障害の状態、異常な血圧、皮膚の状態、自己免疫疾患、眼疾患、高リスク女性における子癇前症性中毒症、男性及び女性における性的不能、アレルギー、喘息、不眠症、うつ病及び関連した状態、循環器疾患及び腫瘍から成る群から選択される前記〔２４〕に記載の方法。
〔２６〕骨疾患が、骨粗鬆症、パジェット病及び骨転移から成る群から選択される前記〔２５〕に記載の方法。
〔２７〕代謝性障害の状態が、肥満、異常な血糖値、異常な血液脂質レベル、糖尿病（Ｉ型又は／及びＩＩ型）及び、糖尿病性網膜症、類壊死性潰瘍及び糖尿病性タンパク尿を含む、糖尿病が誘導する合併症から成る群から選択される前記〔２５〕に記載の方法。
〔２８〕異常な血圧が、高血圧症及び低血圧症から成る群から選択される前記〔２５〕に記載の方法。
〔２９〕皮膚の状態が、乾癬及び乾癬性障害、ニキビ、嚢腫性座瘡、膿性又は発赤の瘤、面皰、丘疹、膿疱、結節、類表皮嚢胞、毛包の角化、異常な血管皮膚病変、母斑、ほくろ（母斑）、軟性線維腫、強皮症、白斑、及び関連する疾患、又は加齢染み（肝斑）から成る群から選択される前記〔２５〕に記載の方法。
〔３０〕自己免疫疾患が、円板状エリテマトーデス、全身性エリテマトーデス（ＳＬＥ）、自己免疫性肝炎、強皮症、シェーグレン症候群、関節リウマチ、多発性筋炎、強皮症、橋本甲状腺炎、若年性糖尿病、アジソン病、白斑、悪性貧血、糸球体腎炎、肺線維症、多発性硬化症（ＭＳ）及びクローン病から成る群から選択される前記〔２５〕に記載の方法。
〔３１〕眼疾患が、緑内障、眼内高血圧、眼科手術後の視力の低下、類嚢胞黄斑部浮腫によって損傷された温血動物の視力、及び白内障から成る群から選択される前記〔２５〕に記載の方法。
〔３２〕循環器疾患が、心臓発作、不安定狭心症、末梢閉塞性動脈疾患及び卒中から成る群から選択される前記〔２５〕に記載の方法。
〔３３〕腫瘍が、良性腫瘍、乳癌、結腸直腸癌、口腔癌、肺又はそのほかの呼吸器系の癌、皮膚癌、子宮癌、膵臓癌、前立腺癌、生殖器の癌、泌尿器の癌、白血病、又はそのほかの血液及びリンパ組織の癌から成る群から選択される前記〔２５〕に記載の方法。
〔３４〕微生物関連の状態が、疼痛、外傷及び炎症関連の状態から成る群から選択される前記〔２４〕に記載の方法。
〔３５〕炎症関連の状態が、前立腺の炎症（前立腺炎）、前立腺膀胱炎、前立腺肥大線維症、痔、川崎症候群、胃腸炎、１型膜増殖性糸球体腎炎、バーター症候群、慢性ブドウ膜炎、強直性脊椎炎、血友病性関節症、炎症性の痔、放射線照射後の（人工造設の）直腸炎、慢性潰瘍性大腸炎、炎症性大腸疾患、腺窩炎、歯周病、関節炎、及び肝臓、肺、胃、脳、腎臓、心臓、耳、眼、鼻、口、舌、結腸、膵臓、胆嚢、十二指腸、直腸、胃、結腸直腸、腸、静脈、呼吸器系、血管、肛門直腸から成る群から選択される臓器における炎症状態、並びに肛門掻痒から成る群から選択される前記〔３４〕に記載の方法。
〔３６〕神経ペプチド関連の状態が、アルツハイマー病及びパーキンソン病から成る群から選択される前記〔２４〕に記載の方法。
〔３７〕経口の、腸管の、頬内の、鼻内の、局所の、直腸の、膣内の、エアゾールの、経粘膜の、表皮の、経皮の、皮内の、眼内の、肺内の、皮下の及び非経口の投与から選択される経路を介して組成物が生物対象に投与される前記〔２３〕に記載の方法。
〔３８〕ペプチドが、アンギオテンシン、アンギオテンシンＩＩの拮抗剤、アンギオテンシンＩＩＡＴ２受容体、抗菌ペプチド、抗オキシトシン、ホルモン、抗利尿ホルモン、副腎皮質刺激ホルモン、抗菌ペプチド、抗炎症性ペプチド、ブラジキニン、ブラジキニンの拮抗剤、エンドセリンペプチド、エンドセリンペプチドの拮抗剤、ガストリン、カルシトニン、メラノーマ関連の抗原ペプチド、ラミニンペプチド、フィブリノーゲンペプチド、ＥＡＥ誘導ペプチド、成長因子、成長ホルモン放出ペプチド、ソマトスタチン、ホルモン放出ホルモン、黄体形成ホルモン放出ホルモン、神経ペプチド、メラニン形成細胞刺激ホルモン、睡眠誘導ペプチド、アミロイドペプチド、ツフトシン、レトロインバルソ型ツフトシン、エンテロスタチン、メラノコルチンＩＩ，及びオピオイドペプチド及び模倣体から成る群から選択される前記〔２３〕に記載の方法。
〔３９〕エンテロスタチンが、Ｖａｌ－Ｐｒｏ－Ａｓｐ－Ｐｒｏ－Ａｒｇ（ＶＰＤＰＲ）、Ｖａｌ－Ｐｒｏ－Ｇｌｙ－Ｐｒｏ－Ａｒｇ（ＶＰＧＰＲ）及びＡｌａ－Ｐｒｏ－Ｇｌｙ－Ｐｒｏ－Ａｒｇ （ＡＰＧＰＲ）から成る群から選択される前記〔３８〕に記載の方法。
〔４０〕オピオイドペプチドが、Ｍｅｔ－エンケファリン（Ｈ－Ｔｙｒ－Ｇｌｙ－Ｇｌｙ－Ｐｈｅ－Ｍｅｔ－ＯＨ）、Ｌｅｕ－エンケファリン（Ｈ－Ｔｙｒ－Ｇｌｙ－Ｇｌｙ－Ｐｈｅ－Ｌｅｕ－ＯＨ）、Ｈ－Ｔｙｒ－Ｄ－Ａｌａ－Ｇｌｙ－Ｎ－Ｍｅ－Ｐｈｅ－Ｍｅｔ（Ｏ）－ＯＬ及びＨ－Ｔｙｒ－Ｄ－Ａｌａ－Ｇｌｙ－Ｐｈｅ－Ｌｅｕ－ＯＨ）から成る群から選択される前記〔３８〕に記載の方法。
〔４１〕ペプチドＨＰＣの固相合成法であって、
（ａ）化学的に修飾された樹脂を提供すること；
（ｂ）ペプチドＨＰＣに従って所望されるように天然の又は修飾されたアミノ酸残基すべてのカルボキシル基を保護基によって保護してＣＯＯＨ－保護のアミノ酸残基を提供すること；
（ｃ）ペプチドＨＰＣのＮ末端にてＣＯＯＨ－保護のアミノ酸残基を化学的に修飾された樹脂に結合させてアミノ酸残基１つを有する不動化されたＣＯＯＨ－保護のペプチドＨＰＣ前駆体を提供すること；
（ｄ）脱保護試薬を用いて、不動化されたＣＯＯＨ－保護のペプチドＨＰＣ前駆体の保護カルボキシル基を脱保護して、アミノ酸残基１つを有する不動化されたＣＯＯＨ－非保護のペプチドＨＰＣ前駆体を提供すること；
（ｅ）Ｃ末端アミノ酸残基を除いてすべてのアミノ酸を有する不動化されたＣ－非保護のペプチドＨＰＣ前駆体が提供されるまで、ペプチドＨＰＣのＣＯＯＨ－保護のアミノ酸残基を用いて工程ｃ）とｄ）を繰り返すこと；
（ｆ）共有結合を介してＣ末端アミノ酸残基をＲ _T に連結し、修飾されたＣ末端アミノ酸を提供すること、その際、Ｒ _T は、置換及び非置換のアルキル基、置換及び非置換のシクロアルキル基、置換及び非置換のヘテロシクロアルキル基、置換及び非置換のアルキルオキシ基、置換及び非置換のアルケニル基、置換及び非置換のアルキニル基、置換及び非置換のアリール基、置換及び非置換のヘテロアリール基、前記〔８〕で定義されたような構造Ｎａ，構造Ｎｂ，構造Ｎｃ，構造Ｎｄ，構造Ｎｅ，構造Ｎｆ，構造Ｎｇ，構造Ｎｈ，構造Ｎｉ，構造Ｎｊ，構造Ｎｋ，構造Ｎｌ，構造Ｎｍ，構造Ｎｎ，構造Ｎｏ，構造Ｎｐ，構造Ｎｑ，及び構造Ｎｒから成る群から選択され：
（ｇ）工程ｅ）から得られる不動化されたＣ－非保護のペプチドＨＰＣ前駆体に修飾されたＣ末端アミノ酸を結合して不動化ペプチドＨＰＣを提供すること；
ｈ）樹脂から不動化ペプチドＨＰＣを解放してペプチドＨＰＣを提供することを
含む合成法。
〔４２〕使用される樹脂が、塩化トリチル樹脂及び炭酸エステル樹脂から成る群から選択される前記〔４１〕に記載の合成法。
〔４３〕保護基が、２－（４－ニトロフェニルスルホニル）エチル基及び９－フルオレニルメチル基から成る群から選択される前記〔４１〕に記載の合成法。
〔４４〕カップリング反応が、ＨＢＴＵ／ＤＩＰＥＡ／ＨＯＢｔ、ＴＢＴＵ／ＤＩＰＥＡ／ＨＯＢｔ、ＢＯＰ／ＤＩＰＥＡ／ＨＯＢｔ、ＨＡＴＵ／ＤＩＰＥＡ／ＨＯＢｔ及びＤＩＣ／ＨＯＢ及びそれらの組み合わせから成る群から選択されるカップリング試薬の存在下で行われる前記〔４１〕に記載の合成法。
〔４５〕経皮治療用塗布システムであって、その親化合物によって治療可能な状態を治療するための活性物質として前記〔９〕、〔１０〕、〔１１〕、〔１２〕又は１３に記載の化合物又は組成物を含み、システムは、水、エタノール、イソプロパノール、アセトン、ＤＭＳＯ、ＤＭＦ及びそれらの組み合わせから成る群から選択される溶媒をさらに含むスプレー又は塗布して用いる溶液である経皮治療用塗布システム。
〔４６〕経皮治療用塗布システムであって、その親化合物によって治療可能な状態を治療するための活性物質として前記〔９〕、〔１０〕、〔１１〕、〔１２〕又は１３に記載の化合物又は組成物を含み、システムはさらに、活性物質を含有するマトリクス層と非透過性の裏打層を含む主部を含む経皮治療用塗布システム。
〔４７〕主部が貼付剤又は帯具である前記〔４６〕に記載の経皮治療用塗布システム。
〔４８〕主部が皮膚に向いた透過性の底部を含む活性物質のリザーバであり、放出速度を制御することによって、システムは有効成分又は有効成分の代謝体が最適な治療用血中レベルに常に達し、有効性を高め、有効成分又は有効成分の代謝体の副作用を軽減することを可能にする前記〔４６〕に記載の経皮治療用塗布システム。 Opioid peptides are natural peptides produced by animals and are not stable in biological systems. They are not addictive and are for the treatment of pain due to toothache, headache, arthritis, other inflammations, fever, cancer, dysmenorrhea, and acute migraines, as well as for the treatment of drug abuse.
The corresponding parent peptides of the HPPs/HOCs that appeared in the examples are listed below in Table D.

Another aspect of the present invention may be as follows.
[1] A highly permeable composition of a peptide or peptide-related compound,
(a) a functional unit;
(b) a linker and
(c) including a transport unit;
the functional unit is covalently attached to the transport unit via a linker;
the functional unit comprises a portion of a peptide or peptide-related compound;
the transport unit contains a protonatable amine group,
A hyperpermeable composition, wherein the linker comprises a chemical bond that can be cleaved after the hyperpermeable composition crosses one or more biological barriers.
[2] The above-mentioned [1], wherein the chemical bond is selected from the group consisting of a covalent bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a carbonate bond, a carbamate bond, a phosphate bond, and an oxime bond. Highly penetrating composition.
[3] The highly permeable composition of [1] above, wherein the portion of the peptide or peptide-related compound is converted to the peptide or peptide-related compound upon cleavage of the cleavable bond.
[4] The highly permeable composition of [1] above, wherein the functional unit comprises a lipophilic derivative of a peptide or peptide-related compound portion.
[5] The high permeability according to [4] above, wherein the lipophilic derivative is selected from the group consisting of carbonates, amides, carbamates, N-Mannich bases, ethers, thioethers, thioesters, phosphates, oximes and imines. Composition.
[6] The high permeability of [1] above, wherein the peptide or peptide-related compound is selected from the group consisting of peptides, peptide metabolites, agents capable of being metabolized to peptides or peptide metabolites, and analogues thereof. Composition.
[7] the protonatable amine group is selected from the group consisting of substituted and unsubstituted primary amine groups, substituted and unsubstituted secondary amine groups, and substituted and unsubstituted tertiary amine groups [ 1].
[8] The protonatable amine group is unique or structure Na, structure Nb, structure Nc, structure Nd, structure Ne, structure Nf, structure Ng, structure Nh, structure Ni, structure Nj, structure Nk, structure Nl, structure Nm, structure Nn, structure No, structure Np, structure Nq, and structure Nr:

including stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein
R ₁₁ to R ₁₆ are independently none, H, CH ₂ COOR ₁₁ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted aryl , substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide wherein carbon or hydrogen may be further independently replaced by O, S, P, NR ₁₁ or other pharmaceutically acceptable groups. thing.
[9] the following chemical structure

Structure L-1
comprising stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein:
F is structure F-1:

a portion of a peptide or peptide-related compound having
Each A ₁ to A _m is independently 2-naphthylalanine, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted Aryl, substituted and unsubstituted heteroaryl residues, structure A and structure B:

Structure A

Structure B
selected from the group consisting of;
each p of each A ₁ -A _m is an independently selected integer;
Z _A-1 at each carbon of each A 1 _to Am _, Z _A-2 , Z _NT , Z _CT-1 and Z _CT-2 for each A ₁ to _Am are independently H, CH ₃ , C2H5 _{, C3H7} , CF3, C2F5, _{C3F7 ,} substituted and unsubstituted alkyl _, substituted _{and unsubstituted} cycloalkyl , _substituted and unsubstituted heterocycloalkyl, substituted and _{unsubstituted} substituted and unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted perfluoroalkyl, and substituted and unsubstituted is selected from the group consisting of alkyl halides of
R _A at each carbon of A ₁ to A _m , R _B , R _NT and R _CT at each carbon of A ₁ to A _m are substituted and unsubstituted imidazolyl, substituted and unsubstituted guanidino, substituted and unsubstituted substituted and unsubstituted carboxyl, substituted and unsubstituted carboxamide, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and from the groups of unsubstituted alkylamino, substituted and unsubstituted alkylcarbonyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl selected from the group consisting of;
When p in A ₁ to A _m is an integer of 2 or more, R _A or R _B on each carbon may be the same or different, and Z _A-1 on each carbon is the same may be one or the other;
Amino and carboxy functional groups in the peptide chain may further form lactam bridges;
Thiol groups may further form disulfide bridges;
T _B , T _C and T _N of each A ₁ -A _m are independently: None, H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted unsubstituted alkyloxy, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, structure Na, structure Nb, structure Nc, structure Nd, structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr:

is selected from the group consisting of
Each R ₁₁ to R ₁₆ is independently none, H, CH ₂ COOR ₁₁ , substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, substituted and unsubstituted consisting of aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide is selected from the group wherein carbon or hydrogen may be further independently replaced by O, S, P, NR ₁₁ or other pharmaceutically acceptable groups;
L _1B , L _1C and L _1N of each A ₁ to A _m are none, O, S, -N(L ₃ )-, -N(L ₃ )-CH ₂ -O, -N(L ₃ )- is selected from the group consisting of CH ₂ -N(L ₅ )-, -O-CH ₂ -O-, -O-CH(L ₃ )-O and -S-CH(L ₃ )-O-;
L _2B , L _2C and L _2N of each A ₁ to A _m are none, O, S, -N(L ₃ )-, -N(L ₃ )-CH ₂ -O, -N(L ₃ )- CH ₂ —N(L ₅ )—, —O—CH ₂ —O—, —O—CH(L ₃ )—O, —S—CH(L ₃ )—O— , —OL ₃ —, — is selected from the group consisting of NL _{3 -, -SL 3} - _, -N(L 3 ₎ -L ₅ - and L ₃ :
L _4B of each A ₁ to A _m , L _4C and L _4N is independently none, C=O, C=S,

as well as

is selected from the group consisting of:
L3 and _L5 are independently none , _H , CH2COOL6 , _{substituted _ _ _ _} _ _{_} _ _ _{_} _ _{_ _ _} _ _{_} and unsubstituted alkyl group, substituted and unsubstituted cycloalkyl group, substituted and unsubstituted heterocycloalkyl group, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and selected from the group consisting of unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halides, wherein carbon or hydrogen are further independently O, may be replaced by S, P, NL3 _or other pharmaceutically acceptable groups;
L ₆ is H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted aryl; from the group consisting of substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide selected wherein carbon or hydrogen is further independently O, S, N, P(O)OL6 _, CH=CH, C[identical to]C, CHL6, CL6L7 _, aryl _, heteroaryl _or cyclic may be replaced by the group of;
L ₇ is H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted aryl; from the group consisting of substituted and unsubstituted heteroaryl, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide selected wherein carbon or hydrogen is further independently O, S, N, P(O)OL6 _, CH=CH, C[identical to]C, CHL6, CL6L7 _, aryl _, heteroaryl _or cyclic may be replaced by the group of
Highly penetrating composition.
[10] The highly permeable composition according to [9] above, wherein the peptide is selected from the group consisting of enterostatin, melanocortin II and opioid peptides.
[11] Structure 2, Structure 3, Structure 4, Structure 5, Structure 6, Structure 7, Structure 8, Structure 9, Structure 10, Structure 11, Structure 12, Structure 13, Structure 14, Structure 15 as shown in FIG. , Structure 16, Structure 17, Structure 18, Structure 19, Structure 20, Structure 21, Structure 22, Structure 23, Structure 24, Structure 25, Structure 26, Structure 27, Structure 28, Structure 37, Structure 38, Structure 39, Structure 40, structure 41, structure 42, structure 43, structure 44, structure 45, structure 46, structure 47, structure 48, structure 49, structure 50, structure 51, structure 52, structure 53, structure 54, structure 55, structure 56, structure 57, structure 58, structure 59, structure 60, structure 61, structure 62, structure 63, structure 64, structure 65, structure 66, structure 67, structure 68, structure 69, structure 70, structure 71, structure 72, structure 73 , Structure 74, Structure 75, Structure 76, Structure 77, Structure 78, Structure 79, Structure 80, Structure 81, Structure 82, Structure 83, Structure 84, Structure 85, Structure 86, Structure 87, Structure 88, Structure 89, Structure 90, structure 91, structure 92, structure 93, structure 94, structure 95, structure 96, structure 97, structure 98, structure 99, structure 100, structure 101, structure 102, structure 103, structure 104, structure 105, structure 106, structure 107, structure 108, structure 109, structure 110, structure 111, structure 112, structure 113, structure 114, structure 115, structure 116, structure 117, structure 118, structure 119, structure 120, structure 121, structure 122, structure 123 , structure 124, structure 125, structure 126, structure 127, structure 128, structure 137, structure 138, structure 139, structure 140, structure 141, structure 142, structure 143, structure 144, structure 145, structure 146, structure 147, structure 148, structure 149, structure 150, structure 151, structure 152, structure 153, structure 154, structure 155, structure 156, structure 157, structure 158, structure 159, structure 160, structure 161, structure 162, structure 163, structure 164, Structure 165, Structure 166, Structure 167, Structure 168, Structure 169, Structure 170, Structure 171, Structure 172, Structure 173, Structure 174, Structure 175, Structure 176, Structure 177, Structure 178, Structure 179, Structure 180, Structure 181 , Structure 182, Structure 183, Structure 184, Structure 185, Structure 186, Structure 187, Structure 188, Structure 189, Structure 190, Structure 191, Structure 192, Structure 193, Structure 194, Structure 195, Structure 196, Structure 197, Structure 198, Structure 199, Structure 200, Structure 201, Structure 202, Structure 203, Structure 204, Structure 205, Structure 206, Structure 207, Structure 208, Structure 209, Structure 210, Structure 211, Structure 212, Structure 213, Structure 214, Structure 215 , structure 216, structure 217, structure 218, structure 219, structure 220, structure 221, structure 222, structure 223, structure 224, structure 225, structure 226, structure 227, structure 228, structure 237, structure 238, structure 239, structure 240, structure 241, structure 242, structure 243, structure 244, structure 245, structure 246, structure 247, structure 248, structure 249, structure 250, structure 251, structure 252, structure 253, structure 254, structure 255, structure 256, Structure 257, Structure 258, Structure 259, Structure 260, Structure 261, Structure 262, Structure 263, Structure 264, Structure 265, Structure 266, Structure 267, Structure 268, Structure 269, Structure 270, Structure 271, Structure 272, Structure 273 , structure 274, structure 275, structure 276, structure 277, structure 278, structure 279, structure 280, structure 281, structure 282, structure 283, structure 284, structure 285, structure 286, structure 287, structure 288, structure 289, structure 290, structure 291, structure 292, structure 293, structure 294, structure 295, structure 296, structure 297, structure 298, structure 299, structure 300, structure 301, structure 302, structure 303, structure 304, structure 305, structure 306, structure 307, structure 308, structure 309, structure 310, structure 311, structure 312, structure 313, structure 314, structure 315, structure 316, structure 317, structure 318, structure 319, structure 320, structure 321, structure 322, structure 323 , structure 324, structure 325, structure 326, structure 327, structure 328, structure 337, structure 338, structure 339, structure 340, structure 341, structure 342, structure 343, structure 344 and structure 345; , including stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein:
R is H, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, substituted and unsubstituted alkylamino, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues of
X, X4 , X5 _{, X6} , _X7 , X8 , _X9 , _{X10 ,} X21 _, X22 _, X23 _, X24 _, X25, _X26 and _X27 are _{independently} C ₌ O, C=S, COO, CSO, CH2OCO , COOCH2OCO, COCH2OCO , CH2 _{- O -} CH ₍ CH2OR4 ) ₂ , CH2 _{- O -} CH _{( CH2OCOR4} ) ₂ , selected from the group consisting of SO2 , PO ₍ OR), NO, O, S, NR5 _and nothing;
R1 , _R2 , _R4 , R5 , _{R6 ,} R7 , R8 , _R9 , R10 _{, R21} , _R22 , _R23 , _{R24 , R25} , _R26 and _{R27 are independently} H, O, NO2 _, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl groups, substituted and unsubstituted heterocycloalkyl groups, substituted and unsubstituted alkoxy, substituted and unsubstituted alkylthio, selected from the group consisting of substituted and unsubstituted alkylamino, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues;
Ar is selected from the group consisting of phenyl, 2′-naphthyl, 4-iodophenyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl residues;
HA is free, hydrochloride, hydrobromide, hydroiodide, nitric acid, sulfuric acid, bisulfate, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, Tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucaronic acid, sugar acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid , p-toluenesulfonic acid, or pamoic acid
The highly permeable composition of the above [9].
[12] comprising a structure selected from the group consisting of Structure 1a, Structure 1b, Structure 1c, Structure 1d, Structure 1e, Structure 1f, Structure 1g, and Structure 1h;

Structure 1a

Structure 1b

structure 1c

structure 1d

Structure 1e

structure 1f

structure 1g

structure 1h
including stereoisomers thereof and pharmaceutically acceptable salts thereof, wherein
X4 , X5 _, X6 , X7, X8 , X9 , _{R4 ,} R5 _, R6 _, R7 , _{R8 ,} R9 _and HA _are as defined _in [ ₁₁ ] above [9 _] high permeability composition.
[13] A pharmaceutical composition comprising the highly permeable composition of [9] above and a pharmaceutically acceptable carrier.
[14] The pharmaceutical composition of [13] above, wherein the pharmaceutically acceptable carrier is polar.
[15] The pharmaceutical composition of [13] above, wherein the pharmaceutically acceptable carrier is selected from the group consisting of alcohol, acetone, ester, water and aqueous solutions.
[16] A method for permeating a biobarrier, comprising administering the pharmaceutical composition of [13] above to the biobarrier.
[17] A method of screening a peptide or peptide-related compound HPP for a desired property, comprising the steps of:
(1) covalently attaching a functional unit comprising a peptide or peptide-related compound to a transport unit via a linker to form a test composition;
(2) administering a test composition to a biological subject or biological barrier;
(3) determining whether the test composition has the desired properties;
How to include.
[18] Desired characteristics
(1) the ability of the test composition to penetrate biological barriers;
(2) the ability of the test composition to convert to the parent drug or active agent;
(3) the permeability of the test composition;
(4) efficiency of the test composition; and
(5) Effectiveness of test composition
The method according to [17] above, which is selected from the group consisting of
[19] A method of diagnosing a condition in a biological subject, comprising the steps of:
(1) administering the composition according to [9] above to a biological subject;
(2) detecting the presence, location or amount of the composition in a biological subject;
(3) detecting a condition in a biological subject;
How to include.
[20] The method of [19] above, wherein the composition is labeled.
[21] A method of diagnosing a condition in a biological subject, comprising the steps of:
(1) administering the composition according to [13] above to a biological subject;
(2) detecting the presence, location or amount of the composition in a biological subject;
(3) detecting a condition in a biological subject;
How to include.
[22] The method of [21] above, wherein the composition is labeled.
[23] A method of treating a condition in a biological subject, comprising administering the highly permeable composition of [9] or the pharmaceutical composition of [13] to the biological subject.
[24] the condition is pain, trauma, inflammation-related condition, microbial-related condition, neuropeptide-related condition, hormone-related condition, tumor, abnormal blood pressure, obesity, brain injury, allergy, male and female gender Impotence, metastasis, and other conditions associated with tuftsin, prepartum, postpartum, anti-AD activity, antidiuretic activity, calcium homeostasis, melanocytes, hormone release, platelet aggregation, CNS activity, and phagocytosis The method according to [23] above, which is selected from the group consisting of
[25] Hormone-related condition is menopause, bone disease, growth hormone deficiency, hyperthyroidism, hypothyroidism, metabolic disorder condition, abnormal blood pressure, skin condition, autoimmune disease, eye disease, high risk [24] above, which is selected from the group consisting of pre-eclamptic toxicosis in women, impotence in men and women, allergies, asthma, insomnia, depression and related conditions, cardiovascular diseases and tumors Method.
[26] The method of [25] above, wherein the bone disease is selected from the group consisting of osteoporosis, Paget's disease and bone metastasis.
[27] The condition of metabolic disorder is obesity, abnormal blood glucose level, abnormal blood lipid level, diabetes (type I or/and type II) and diabetic retinopathy, necrotic ulcer and diabetic proteinuria The method according to [25] above, which is selected from the group consisting of complications induced by diabetes, including
[28] The method of [25] above, wherein the abnormal blood pressure is selected from the group consisting of hypertension and hypotension.
[29] The skin condition is psoriasis and psoriatic disorders, acne, cystic acne, purulent or red bumps, comedones, papules, pustules, nodules, epidermoid cysts, keratinization of hair follicles, abnormal vascular skin The method according to [25] above, which is selected from the group consisting of lesions, nevi, moles (nevus), fibroma softness, scleroderma, vitiligo, and related diseases, or age spots (melasma).
[30] Autoimmune disease is discoid lupus erythematosus, systemic lupus erythematosus (SLE), autoimmune hepatitis, scleroderma, Sjögren's syndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto's thyroiditis, juvenile diabetes , Addison's disease, vitiligo, pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS) and Crohn's disease.
[31] the above [25], wherein the eye disease is selected from the group consisting of glaucoma, intraocular hypertension, decreased visual acuity after ophthalmic surgery, visual acuity in warm-blooded animals damaged by cystoid macular edema, and cataracts described method.
[32] The method of [25] above, wherein the cardiovascular disease is selected from the group consisting of heart attack, unstable angina, peripheral occlusive artery disease and stroke.
[33] the tumor is a benign tumor, breast cancer, colorectal cancer, oral cancer, lung or other respiratory cancer, skin cancer, uterine cancer, pancreatic cancer, prostate cancer, genital cancer, urinary cancer, leukemia, Or the method according to [25] above, which is selected from the group consisting of other blood and lymphatic tissue cancers.
[34] The method of [24] above, wherein the microorganism-related condition is selected from the group consisting of pain, trauma, and inflammation-related conditions.
[35] Inflammation-related conditions include prostate inflammation (prostatitis), prostatic cystitis, prostatic hyperplasia fibrosis, hemorrhoids, Kawasaki syndrome, gastroenteritis, type 1 membranous proliferative glomerulonephritis, Bartter's syndrome, chronic uveitis , ankylosing spondylitis, hemophilic arthritis, inflammatory hemorrhoids, post-irradiation (artificial) proctitis, chronic ulcerative colitis, inflammatory bowel disease, cryptitis, periodontal disease, arthritis and liver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum, rectum, stomach, colorectal, bowel, vein, respiratory system, blood vessel, The method according to [34] above, which is selected from the group consisting of an inflammatory condition in an organ selected from the group consisting of the anorectal, and anal pruritus.
[36] The method of [24] above, wherein the neuropeptide-related condition is selected from the group consisting of Alzheimer's disease and Parkinson's disease.
[37] oral, intestinal, buccal, intranasal, topical, rectal, intravaginal, aerosol, transmucosal, epidermal, transdermal, intradermal, intraocular, pulmonary The method of [23] above, wherein the composition is administered to the living subject via a route selected from intra-, subcutaneous and parenteral administration.
[38] the peptide is angiotensin, angiotensin II antagonist, angiotensin II AT2 receptor, antibacterial peptide, antioxytocin, hormone, antidiuretic hormone, adrenocorticotropic hormone, antibacterial peptide, anti-inflammatory peptide, bradykinin, bradykinin antagonist , endothelin peptides, antagonists of endothelin peptides, gastrin, calcitonin, melanoma-associated antigenic peptides, laminin peptides, fibrinogen peptides, EAE-inducing peptides, growth factors, growth hormone-releasing peptides, somatostatin, hormone-releasing hormones, luteinizing hormone-releasing hormones, The above-mentioned [23], which is selected from the group consisting of neuropeptides, melanocyte-stimulating hormone, sleep-inducing peptides, amyloid peptides, tuftsin, retro-invarso-type tuftsin, enterostatin, melanocortin II, and opioid peptides and mimetics Method.
[39] enterostatin is selected from the group consisting of Val-Pro-Asp-Pro-Arg (VPDPR), Val-Pro-Gly-Pro-Arg (VPGPR) and Ala-Pro-Gly-Pro-Arg (APGPR) The method according to [38] above.
[40] the opioid peptide is Met-enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH), Leu-enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH), H-Tyr-D -Ala-Gly-N-Me-Phe-Met(O)-OL and H-Tyr-D-Ala-Gly-Phe-Leu-OH).
[41] A method for solid phase synthesis of peptide HPC, comprising:
(a) providing a chemically modified resin;
(b) protecting the carboxyl groups of all natural or modified amino acid residues with protecting groups to provide COOH-protected amino acid residues as desired according to peptide HPC;
(c) coupling a COOH-protected amino acid residue at the N-terminus of the peptide HPC to a chemically modified resin to provide an immobilized COOH-protected peptide HPC precursor with one amino acid residue; to do;
(d) deprotection of the protected carboxyl groups of the immobilized COOH-protected peptide HPC precursor with a deprotection reagent to yield immobilized COOH-unprotected peptide HPC with one amino acid residue; providing a precursor;
(e) step c with the COOH-protected amino acid residues of the peptide HPC until an immobilized C-unprotected peptide HPC precursor with all amino acids except the C-terminal amino acid residue is provided; ) and d);
(f) linking the C-terminal amino acid residue to _RT via a covalent bond to provide a modified C-terminal amino acid, wherein _RT is a substituted and unsubstituted alkyl group, substituted and unsubstituted The cycloalkyl group, substituted and unsubstituted heterocycloalkyl group, substituted and unsubstituted alkyloxy group, substituted and unsubstituted alkenyl group, substituted and unsubstituted alkynyl group, substituted and unsubstituted aryl group, substituted and unsubstituted unsubstituted heteroaryl group, structure Na, structure Nb, structure Nc, structure Nd, structure Ne, structure Nf, structure Ng, structure Nh, structure Ni, structure Nj, structure Nk, as defined in [8] above, is selected from the group consisting of Structure Nl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq, and Structure Nr:
(g) attaching a modified C-terminal amino acid to the immobilized C-unprotected peptide HPC precursor obtained from step e) to provide immobilized peptide HPC;
h) releasing the immobilized peptide HPC from the resin to provide peptide HPC;
Synthetic methods including.
[42] The synthesis method according to [41] above, wherein the resin used is selected from the group consisting of trityl chloride resin and carbonate ester resin.
[43] The synthetic method of [41] above, wherein the protecting group is selected from the group consisting of a 2-(4-nitrophenylsulfonyl)ethyl group and a 9-fluorenylmethyl group.
[44] the coupling reaction is a coupling reagent selected from the group consisting of HBTU/DIPEA/HOBt, TBTU/DIPEA/HOBt, BOP/DIPEA/HOBt, HATU/DIPEA/HOBt, and DIC/HOB and combinations thereof; The synthesis method according to the above [41] performed in the presence.
[45] The transdermal therapeutic application system of [9], [10], [11], [12] or 13 as an active substance for treating a condition treatable by the parent compound A transdermal therapeutic application that is a spray or spread-on solution comprising a compound or composition, wherein the system further comprises a solvent selected from the group consisting of water, ethanol, isopropanol, acetone, DMSO, DMF, and combinations thereof. system.
[46] The transdermal therapeutic application system according to [9], [10], [11], [12] or 13 as an active substance for treating a condition treatable by the parent compound A transdermal therapeutic application system comprising a compound or composition, the system further comprising a body comprising a matrix layer containing an active agent and an impermeable backing layer.
[47] The percutaneous therapeutic application system of [46], wherein the main part is a patch or bandage.
[48] a reservoir of the active agent comprising a permeable bottom portion facing the skin, and by controlling the rate of release, the system allows the active ingredient or metabolites of the active ingredient to reach optimal therapeutic blood levels; The percutaneous therapeutic application system according to [46] above, which is capable of reaching the target at all times, enhancing efficacy, and reducing side effects of the active ingredient or metabolites of the active ingredient.

Claims (1)

Structures 1b and 1e below:

Structure 1b

Structure 1e
(In each structure, HA is none, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, bisulfuric acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, selected from the group consisting of p-toluenesulfonic acid and pamoic acid)
An analgesic composition comprising a peptide-related compound having a structure selected from the group consisting of:

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